原发性肝癌发生、发展相关基因的研究
|
摘要
原发性肝癌在世界范围内属于常见肿瘤,主要发生于亚洲和撒哈拉以南非洲地区,其中约半数发生于中国。肝癌预后很差,即使根治术后5年生存率仅17%-53%,而且复发率很高。每年新发病例数与同年死亡病例数接近。造成肝癌预后差的原因主要有两个:其一是肝癌对常规的化疗几乎无效;其二是现有的肝癌早期诊断指标存在不足,超过80%的患者就诊时处于进展期或失去手术切除机会。肝癌是多基因参与、多步骤发生的过程。但是目前对肝癌发生、发展中参与基因的了解还很有限,研究肝癌发生、发展的相关基因对阐明肝癌发生的分子机制具有非常重要的意义,对肝癌发生相关基因的深入了解能够为寻找潜在的早期诊断和预后标记及筛选治疗靶点提供有用的信息和依据。
在本课题中,我们使用抑制性差减杂交结合芯片方法鉴定人肝细胞肝癌相关基因,鉴于对人体肝癌研究只能针对某一阶段,而对动物肝癌模型的研究可以系统分析肝癌发生、发展过程中的全基因组表达谱改变,因此,我们使用二乙基亚硝胺诱导方法建立了大鼠肝癌模型,结合Affymetrix基因芯片技术得到了模型大鼠从肝硬化至肝转移阶段的差异表达基因谱。在上述工作基础上,本研究从中选取了一条在四个阶段都高表达的基因(Fn14)进行了在肝癌细胞中的功能初步探讨,得到了一些有意义的结果。
第一部分抑制性差减杂交结合cDNA芯片方法筛选人肝细胞肝癌相关基因
原发性肝细胞肝癌(HCC)的分子遗传学背景目前并不完全清楚。在本课题中,我们使用抑制性差减杂交方法(SSH)结合cDNA芯片分析技术分离和鉴定肝细胞肝癌中的差异基因表达谱,鉴定肝癌组织与癌旁非肿瘤组织差异表达已知基因45条,其中26条为肝癌组织表达上调基因,19条为肝癌组织表达下调基因。这些已知基因表达产物呈现广泛的生物学功能,参与众多生物学过程,诸如蛋白质的转录和生物合成、脂质和蛋白质的代谢、细胞增殖、信号传导等。此外,还发现参与丙酮醛解毒的谷胱甘肽结合蛋白GLO1表达增高以及上调前列腺素E(2)合成的酶PLA2G10在肝癌组织中表达上调。在肝癌组织中发现的下调基因中大多数合成肝脏特异性蛋白(纤维蛋白原、补体、淀粉样蛋白、白蛋白、触珠蛋白、血红素蛋白和α-酸性粘蛋白)。参与生物转化的细胞色素家族成员在肝癌组织中表达下调。一些基因编码产物是酶如醇脱氢酶(ADH1C)、醛脱氢酶(ALDH6A1)、醛缩酶(ALDOB)、精氨酸酶(Arginase)和酯酶(CES1)。同时,我们也分离到锌转运体(Zip14)和功能未知基因ZBTB11(zinc fingerand BTB domain containing 11)在肝癌组织中表达下调。在肝癌组织中有7条未知EST与数据库中序列没有同源性。通过应用SSH结合cDNA芯片技术我们分离鉴定了一些肝癌相关基因,其中一些既往没有相关报道。对这些基因的深入研究为了解肝癌发生发展分子机制提供有用的信息。
第二部分大鼠肝癌模型发生过程中全基因表达谱的分析
为了系统分析肝癌发生、发展过程中全基因表达谱改变,了解其中起重要作用的基因,应用DEN诱导方法建立了大鼠肝癌模型,大鼠模型肝脏病变经过肝脏非特异性损伤、肝脏纤维化和硬化、异型增生结节和肝癌形成和转移阶段。选取正常大鼠肝组织、肝硬化组织(诱癌第12周)、异型增生结节(第14周)、肝癌结节(第16周)以及肺转移大鼠的肝癌组织(第20周)进行Affymetrix基因芯片检测。差异基因表达谱结果显示,肝硬化组织(12周)上调基因681个,下调基因687个;异型增生结节(14周)上调基因857个,下调基因732个;肝癌结节(16周)上调基因1223个,下调基因1016个;肝癌转移阶段(20周)上调基因999个,下调基因906个。四个阶段共同上调基因349个,其中已知基因246个;共同下调基因345个,其中已知基因215个,剩余为推测基因、转录位点和完全未知基因。我们选取部分差异表达基因通过实时荧光定量RT-PCR技术证实了基因芯片结果的可靠性。差异表达基因参与众多的生物学过程和分子功能,包括物质代谢、物质转运、细胞增殖、细胞凋亡、细胞粘附、血管生成等。一些差异表达基因与炎症反应、免疫反应和应激反应相关。因此认为,在肝炎、纤维化和硬化及其相应细胞外基质改变的结构基础上,炎症反应、免疫反应和应激反应为肝癌发生、发展提供了多种细胞因子组成的微环境,众多相关基因改变造成细胞增殖和凋亡之间的不平衡,同时新生血管形成旺盛,因而肝癌发生并逐渐演进。通过系统分析模型大鼠肝癌发生过程中的基因表达谱改变,发现了肝癌发生、发展过程中可能起重要作用的差异表达基因,而且许多基因和肝癌的相关性是既往没有报道的,这些差异基因的发现为寻找肝癌诊断和预后的候选分子和筛选治疗靶点提供了有用的信息和基础。
第三部分Fn14在肝癌细胞中功能的初步探讨
Fn14基因是在模型组大鼠肝硬化组织(12周)、异型增生结节(14周)、早期肝癌结节和肺转移大鼠肝癌结节(20周)中均高表达的基因之一。本实验探讨Fn14对肝癌细胞凋亡和存活的影响及分子机制。建立Fn14过表达细胞模型,细胞核荧光染色和流式细胞仪检测细胞凋亡,MTT方法分析细胞存活率。结果发现Fn14高表达提高肝癌细胞存活率:TRAIL处理pcDNA3.1-Fn14转染细胞存活抑制率11.82%vs TRAIL处理pcDNA3.1转染细胞存活抑制率29.69%(p＜0.05),抵抗TRAIL诱导的肝癌细胞凋亡:TRAIL处理后pcDNA3.1转染细胞凋亡率24.17%vs TRAIL处理后pcDNA3.1-Fn14转染细胞凋亡率8.55%。进一步机制探讨发现,Fn14高表达促进肝癌细胞存活和抵抗TRAIL诱导凋亡是部分依赖于NF-κB活性的:NF-κB活性抑制剂预处理pcDNA3.1-Fn14转染细胞后再经TRAIL诱导细胞存活抑制率29.64%vs不经NF-κB活性抑制剂预处理的pcDNA3.1-Fn14转染细胞直接TRAIL诱导细胞存活抑制率11.82%(p＜0.05);NF-κB活性抑制剂预处理pcDNA3.1-Fn14转染细胞再经TRAIL诱导后细胞凋亡率19.65%vs不经NF-κB活性抑制剂预处理pcDNA3.1-Fn14转染细胞直接TRAIL诱导细胞凋亡率9.82%。因此认为Fn14提高肝癌细胞存活和抵抗细胞毒性剂诱导凋亡,这些功能部分依赖于NF-κB活性。
Primary liver cancer is the fifth most common malignancy worldwide,majorly affecting those in Asia and of sub-Saharan Africa, among which about half of cases are from China.The long-term prognosis of patients undergoing potentially curative hepatic resection is still poor,with reported 5-year survival rates ranging from 17%to 53%. Despite resection with curative intent,the clinical course is variable and recurrence occurs in a high proportion of cases.The number of death from liver cancer per year are almost equal to that of new cases occurred in the same year.The poor prognosis of liver cancer is majorly due to patients' no response to almost all conventional chemotherapy and over 80%patients diagnosed at advanced stage and lost the opportunity for curative resection.Numorous genes play roles in the multi-step development of liver cancer.At present,numerous genes involved in the development of liver cancer remains unclear.Research on the tumor-associated genes of liver cancer could provide clues for searching the potential biomarkers for early diagnosis and prognosis and screening targets for treatment.
In the present study,methods of suppression subtractive hybridization combined cDNA chips were used to identify and screen the differential expression genes in hepatocellular carcinoma.However, samples from the human being only can be obtained from a certain phase, while serial analysis of differential expression genes profiles in the whole process of development of liver cancer could be accomplished through establishment of animal models.Therefore,we established the rat models of liver cancer by DEN and investigated the gene expression profiles of liver tissues from cirrhosis to carcinoma with Affymetrixchip' assisting. Fn14,one upregulated gene persisting from cirrhosis to metastasis in rat models was chosen for further research in liver cancer cells.
Part 1 Identification of differential expression of genes in hepatocellular carcinoma by suppression subtractive hybridization combined cDNA microarray
The genetic background of hepatocellular carcinoma(HCC)has yet to be completely understood.Here,we describe the application of suppression subtractive hybridization(SSH)coupled with cDNA microarray analysis for the isolation and identification of differential expression of genes in HCC.Twenty-six known genes were validated as up-regulated and 19 known genes as down-regulated in HCC.The known genes identified were found to have diverse functions.In addition to the overexpression of AFP,these genes(increased in the presence of HCC) are involved in many processes,such as transcription and protein biosynthesis(HNRPDL,PABPC1,POLR2K,SRP9,SNRPA,and six ribosomal protein genes including RPL8,RPL14,RPL41,RPS5,RPS17, RPS24),the metabolism of lipids and proteins(FADS1,ApoA-Ⅱ,ApoM, FTL),cell proliferation(Syndecan-2,and Annexin A2),and signal transduction(LRRC28 and FMR1).Additionally,a glutathione-binding protein involved in the detoxification of methylglyoxal known as GLO1 and an enzyme which increases the formation of prostaglandin E(2) known as PLA2G10 were up-regulated in HCC.Among the underexpressed genes discovered in HCC,most were responsible for liver-synthesized proteins(fibrinogen,complement species,amyloid, albumin,haptoglobin,hemopexin and orosomucoid).The enzyme implicated in the biotransformation of CYP family members (LOC644587)was decreased.The genes coding enzymes ADH1C, ALDH6A1,ALDOB,Arginase and CES1 were also found.Additionally, we isolated a zinc transporter(Zip14)and a function-unknown gene named ZBTB11(Zinc finger and BTB domain containing 11)which were underexpressed,and seven expression sequence tags deregulated in HCC without signifcant homology reported in the public database.Essentially, by using SSH combined with a cDNA microarray we have identified a number of genes associated with HCC,most of which have not been previously reported.Further characterization of these differentially expressed genes will provide information useful in understanding the genes responsible for the development of HCC.
Part 2 Analysis of genomic expressional profiles in the development of liver cancer models of rats induced by DEN
To explore the key genes involved in the development and progression of liver cancer at global scale,we established the rat models of liver cancer induced by DEN and investigated the gene expression profiles of liver tissues from cirrhosis to carcinoma with Affymetrixchip' assisting.The pathological changes of the livers in rats are processes including non-special injury,fibrosis&cirrhosis,dysplastic nodules,early cancerous nodules and metastasis.The liver tissues of cirrhosis(12~(th) week),the dysplasia nodules at the 14~(th)week,the cancerous nolules at the 16~(th)week and the cancerous nodules from the rats with lung metastasis (20~(th)week)were chosen to investigate the differential expression genes(DEGs)by compared with the liver tissues from the normal rats with Affymetrix chip.The differential expression genes obtained by comparing the signals of 4 groups selected with the signals from the liver tissues of the normal rats,respectively.There are 681 upregulated and 687 downregulated genes in the cirrhosis tissue(12~(th)week);857 upregulated and 732 downregulated genes in the dysplasia nodules(14~(th) week);1223 upregulated and 1016 downregulated genes in the cancerous nodules at the 16~(th)week;999 upregulated and 906 downregulated genes in the cancer tissue at metastatic stage(20~(th)week),respectively.Among all the DEGs,there are 349 upregulated and 345 downregulated genes shared for the 4 stages,among which 246 of 349 upregulated DEGs and 215 of 345 downregulated DEGs are known genes,the remaining are genes inferred or predicted,translocation locus and unknown genes completely.Some differential expression genes were confirmed by the method of real time RT-PCR.The deregulated DEGs play various roles and involve in diverse processes such as metabolism,transport,cell proliferation,apoptosis,cell adhesion,agiogenesis and so on.Some of the DEGs are associated with inflammatory response,immune response and oxidative stress.Upon this,we think that inflammatory response,immune response and oxidative stress provides a niche for liver cells on the changed structure of hepatitis,fibrosis,cirrhosis as well as excellular matrix.The balance between cell proliferation and apoptosis was destroyed due to the deregulation of numerous genes,meanwhile, neovascularization is producive.Therefore,the liver cancer developed and progressed.In the present study,we provide gene expression profiles may play major roles in the development of liver cancer by systemic analysis of profiles of DEGs during the development and progression of liver cancer of rats,which will contribute to the understanding of liver cancer development and offer the opportunity for searching marker of diagnosis and prognosis as well as provide clues for targeting therapy. However,many genes related to liver cancer have not been previously reported.
Part 3 The functional assays of Fn14 in liver cancer cells
In the second part of the thesis,a number of deregulated expression genes were identified in the liver cancer model of rats induced by DEN. Fn14 is one of the up-regulated expression genes occurred persistently from liver cirrhosis to metastastic stage of liver cancer.To explore the roles of Fn14 plays in the development of liver cancer,overexpression of Fn14 in SMMC7721 was established.On the basis of Fn14's overexpression,methods and techniques including MTT, immunoflurence staining and flow cytometry analysis were used to assay the effects of Fn14 on the survival ability and apoptosis of SMMC7721 cells treated by TRAIL.Furthermore,an inhibitor of NF-κB activity was used to determine whether the effects of Fn14 on the survive and apoptosis were dependent on the activation of NF-κB.The results showed that overexpression of Fn14 prompts cellular survive and resists apoptosis induced by TRAIL.Meanwhile,increased expression of Fn14 results in translocation of p65 subunit of NF-κB to the nucleus from cytoplasm.Furthermore,increased survive and resisted apoptosis of cells induced by upregulated expression of Fn14 was dependent on the activation of NF-κB.The results implied that Fn14 may be potential marker of diagnosis and prognosis and serve as a target for therapy of liver cancer.
在本课题中,我们使用抑制性差减杂交结合芯片方法鉴定人肝细胞肝癌相关基因,鉴于对人体肝癌研究只能针对某一阶段,而对动物肝癌模型的研究可以系统分析肝癌发生、发展过程中的全基因组表达谱改变,因此,我们使用二乙基亚硝胺诱导方法建立了大鼠肝癌模型,结合Affymetrix基因芯片技术得到了模型大鼠从肝硬化至肝转移阶段的差异表达基因谱。在上述工作基础上,本研究从中选取了一条在四个阶段都高表达的基因(Fn14)进行了在肝癌细胞中的功能初步探讨,得到了一些有意义的结果。
第一部分抑制性差减杂交结合cDNA芯片方法筛选人肝细胞肝癌相关基因
原发性肝细胞肝癌(HCC)的分子遗传学背景目前并不完全清楚。在本课题中,我们使用抑制性差减杂交方法(SSH)结合cDNA芯片分析技术分离和鉴定肝细胞肝癌中的差异基因表达谱,鉴定肝癌组织与癌旁非肿瘤组织差异表达已知基因45条,其中26条为肝癌组织表达上调基因,19条为肝癌组织表达下调基因。这些已知基因表达产物呈现广泛的生物学功能,参与众多生物学过程,诸如蛋白质的转录和生物合成、脂质和蛋白质的代谢、细胞增殖、信号传导等。此外,还发现参与丙酮醛解毒的谷胱甘肽结合蛋白GLO1表达增高以及上调前列腺素E(2)合成的酶PLA2G10在肝癌组织中表达上调。在肝癌组织中发现的下调基因中大多数合成肝脏特异性蛋白(纤维蛋白原、补体、淀粉样蛋白、白蛋白、触珠蛋白、血红素蛋白和α-酸性粘蛋白)。参与生物转化的细胞色素家族成员在肝癌组织中表达下调。一些基因编码产物是酶如醇脱氢酶(ADH1C)、醛脱氢酶(ALDH6A1)、醛缩酶(ALDOB)、精氨酸酶(Arginase)和酯酶(CES1)。同时,我们也分离到锌转运体(Zip14)和功能未知基因ZBTB11(zinc fingerand BTB domain containing 11)在肝癌组织中表达下调。在肝癌组织中有7条未知EST与数据库中序列没有同源性。通过应用SSH结合cDNA芯片技术我们分离鉴定了一些肝癌相关基因,其中一些既往没有相关报道。对这些基因的深入研究为了解肝癌发生发展分子机制提供有用的信息。
第二部分大鼠肝癌模型发生过程中全基因表达谱的分析
为了系统分析肝癌发生、发展过程中全基因表达谱改变,了解其中起重要作用的基因,应用DEN诱导方法建立了大鼠肝癌模型,大鼠模型肝脏病变经过肝脏非特异性损伤、肝脏纤维化和硬化、异型增生结节和肝癌形成和转移阶段。选取正常大鼠肝组织、肝硬化组织(诱癌第12周)、异型增生结节(第14周)、肝癌结节(第16周)以及肺转移大鼠的肝癌组织(第20周)进行Affymetrix基因芯片检测。差异基因表达谱结果显示,肝硬化组织(12周)上调基因681个,下调基因687个;异型增生结节(14周)上调基因857个,下调基因732个;肝癌结节(16周)上调基因1223个,下调基因1016个;肝癌转移阶段(20周)上调基因999个,下调基因906个。四个阶段共同上调基因349个,其中已知基因246个;共同下调基因345个,其中已知基因215个,剩余为推测基因、转录位点和完全未知基因。我们选取部分差异表达基因通过实时荧光定量RT-PCR技术证实了基因芯片结果的可靠性。差异表达基因参与众多的生物学过程和分子功能,包括物质代谢、物质转运、细胞增殖、细胞凋亡、细胞粘附、血管生成等。一些差异表达基因与炎症反应、免疫反应和应激反应相关。因此认为,在肝炎、纤维化和硬化及其相应细胞外基质改变的结构基础上,炎症反应、免疫反应和应激反应为肝癌发生、发展提供了多种细胞因子组成的微环境,众多相关基因改变造成细胞增殖和凋亡之间的不平衡,同时新生血管形成旺盛,因而肝癌发生并逐渐演进。通过系统分析模型大鼠肝癌发生过程中的基因表达谱改变,发现了肝癌发生、发展过程中可能起重要作用的差异表达基因,而且许多基因和肝癌的相关性是既往没有报道的,这些差异基因的发现为寻找肝癌诊断和预后的候选分子和筛选治疗靶点提供了有用的信息和基础。
第三部分Fn14在肝癌细胞中功能的初步探讨
Fn14基因是在模型组大鼠肝硬化组织(12周)、异型增生结节(14周)、早期肝癌结节和肺转移大鼠肝癌结节(20周)中均高表达的基因之一。本实验探讨Fn14对肝癌细胞凋亡和存活的影响及分子机制。建立Fn14过表达细胞模型,细胞核荧光染色和流式细胞仪检测细胞凋亡,MTT方法分析细胞存活率。结果发现Fn14高表达提高肝癌细胞存活率:TRAIL处理pcDNA3.1-Fn14转染细胞存活抑制率11.82%vs TRAIL处理pcDNA3.1转染细胞存活抑制率29.69%(p＜0.05),抵抗TRAIL诱导的肝癌细胞凋亡:TRAIL处理后pcDNA3.1转染细胞凋亡率24.17%vs TRAIL处理后pcDNA3.1-Fn14转染细胞凋亡率8.55%。进一步机制探讨发现,Fn14高表达促进肝癌细胞存活和抵抗TRAIL诱导凋亡是部分依赖于NF-κB活性的:NF-κB活性抑制剂预处理pcDNA3.1-Fn14转染细胞后再经TRAIL诱导细胞存活抑制率29.64%vs不经NF-κB活性抑制剂预处理的pcDNA3.1-Fn14转染细胞直接TRAIL诱导细胞存活抑制率11.82%(p＜0.05);NF-κB活性抑制剂预处理pcDNA3.1-Fn14转染细胞再经TRAIL诱导后细胞凋亡率19.65%vs不经NF-κB活性抑制剂预处理pcDNA3.1-Fn14转染细胞直接TRAIL诱导细胞凋亡率9.82%。因此认为Fn14提高肝癌细胞存活和抵抗细胞毒性剂诱导凋亡,这些功能部分依赖于NF-κB活性。
Primary liver cancer is the fifth most common malignancy worldwide,majorly affecting those in Asia and of sub-Saharan Africa, among which about half of cases are from China.The long-term prognosis of patients undergoing potentially curative hepatic resection is still poor,with reported 5-year survival rates ranging from 17%to 53%. Despite resection with curative intent,the clinical course is variable and recurrence occurs in a high proportion of cases.The number of death from liver cancer per year are almost equal to that of new cases occurred in the same year.The poor prognosis of liver cancer is majorly due to patients' no response to almost all conventional chemotherapy and over 80%patients diagnosed at advanced stage and lost the opportunity for curative resection.Numorous genes play roles in the multi-step development of liver cancer.At present,numerous genes involved in the development of liver cancer remains unclear.Research on the tumor-associated genes of liver cancer could provide clues for searching the potential biomarkers for early diagnosis and prognosis and screening targets for treatment.
In the present study,methods of suppression subtractive hybridization combined cDNA chips were used to identify and screen the differential expression genes in hepatocellular carcinoma.However, samples from the human being only can be obtained from a certain phase, while serial analysis of differential expression genes profiles in the whole process of development of liver cancer could be accomplished through establishment of animal models.Therefore,we established the rat models of liver cancer by DEN and investigated the gene expression profiles of liver tissues from cirrhosis to carcinoma with Affymetrixchip' assisting. Fn14,one upregulated gene persisting from cirrhosis to metastasis in rat models was chosen for further research in liver cancer cells.
Part 1 Identification of differential expression of genes in hepatocellular carcinoma by suppression subtractive hybridization combined cDNA microarray
The genetic background of hepatocellular carcinoma(HCC)has yet to be completely understood.Here,we describe the application of suppression subtractive hybridization(SSH)coupled with cDNA microarray analysis for the isolation and identification of differential expression of genes in HCC.Twenty-six known genes were validated as up-regulated and 19 known genes as down-regulated in HCC.The known genes identified were found to have diverse functions.In addition to the overexpression of AFP,these genes(increased in the presence of HCC) are involved in many processes,such as transcription and protein biosynthesis(HNRPDL,PABPC1,POLR2K,SRP9,SNRPA,and six ribosomal protein genes including RPL8,RPL14,RPL41,RPS5,RPS17, RPS24),the metabolism of lipids and proteins(FADS1,ApoA-Ⅱ,ApoM, FTL),cell proliferation(Syndecan-2,and Annexin A2),and signal transduction(LRRC28 and FMR1).Additionally,a glutathione-binding protein involved in the detoxification of methylglyoxal known as GLO1 and an enzyme which increases the formation of prostaglandin E(2) known as PLA2G10 were up-regulated in HCC.Among the underexpressed genes discovered in HCC,most were responsible for liver-synthesized proteins(fibrinogen,complement species,amyloid, albumin,haptoglobin,hemopexin and orosomucoid).The enzyme implicated in the biotransformation of CYP family members (LOC644587)was decreased.The genes coding enzymes ADH1C, ALDH6A1,ALDOB,Arginase and CES1 were also found.Additionally, we isolated a zinc transporter(Zip14)and a function-unknown gene named ZBTB11(Zinc finger and BTB domain containing 11)which were underexpressed,and seven expression sequence tags deregulated in HCC without signifcant homology reported in the public database.Essentially, by using SSH combined with a cDNA microarray we have identified a number of genes associated with HCC,most of which have not been previously reported.Further characterization of these differentially expressed genes will provide information useful in understanding the genes responsible for the development of HCC.
Part 2 Analysis of genomic expressional profiles in the development of liver cancer models of rats induced by DEN
To explore the key genes involved in the development and progression of liver cancer at global scale,we established the rat models of liver cancer induced by DEN and investigated the gene expression profiles of liver tissues from cirrhosis to carcinoma with Affymetrixchip' assisting.The pathological changes of the livers in rats are processes including non-special injury,fibrosis&cirrhosis,dysplastic nodules,early cancerous nodules and metastasis.The liver tissues of cirrhosis(12~(th) week),the dysplasia nodules at the 14~(th)week,the cancerous nolules at the 16~(th)week and the cancerous nodules from the rats with lung metastasis (20~(th)week)were chosen to investigate the differential expression genes(DEGs)by compared with the liver tissues from the normal rats with Affymetrix chip.The differential expression genes obtained by comparing the signals of 4 groups selected with the signals from the liver tissues of the normal rats,respectively.There are 681 upregulated and 687 downregulated genes in the cirrhosis tissue(12~(th)week);857 upregulated and 732 downregulated genes in the dysplasia nodules(14~(th) week);1223 upregulated and 1016 downregulated genes in the cancerous nodules at the 16~(th)week;999 upregulated and 906 downregulated genes in the cancer tissue at metastatic stage(20~(th)week),respectively.Among all the DEGs,there are 349 upregulated and 345 downregulated genes shared for the 4 stages,among which 246 of 349 upregulated DEGs and 215 of 345 downregulated DEGs are known genes,the remaining are genes inferred or predicted,translocation locus and unknown genes completely.Some differential expression genes were confirmed by the method of real time RT-PCR.The deregulated DEGs play various roles and involve in diverse processes such as metabolism,transport,cell proliferation,apoptosis,cell adhesion,agiogenesis and so on.Some of the DEGs are associated with inflammatory response,immune response and oxidative stress.Upon this,we think that inflammatory response,immune response and oxidative stress provides a niche for liver cells on the changed structure of hepatitis,fibrosis,cirrhosis as well as excellular matrix.The balance between cell proliferation and apoptosis was destroyed due to the deregulation of numerous genes,meanwhile, neovascularization is producive.Therefore,the liver cancer developed and progressed.In the present study,we provide gene expression profiles may play major roles in the development of liver cancer by systemic analysis of profiles of DEGs during the development and progression of liver cancer of rats,which will contribute to the understanding of liver cancer development and offer the opportunity for searching marker of diagnosis and prognosis as well as provide clues for targeting therapy. However,many genes related to liver cancer have not been previously reported.
Part 3 The functional assays of Fn14 in liver cancer cells
In the second part of the thesis,a number of deregulated expression genes were identified in the liver cancer model of rats induced by DEN. Fn14 is one of the up-regulated expression genes occurred persistently from liver cirrhosis to metastastic stage of liver cancer.To explore the roles of Fn14 plays in the development of liver cancer,overexpression of Fn14 in SMMC7721 was established.On the basis of Fn14's overexpression,methods and techniques including MTT, immunoflurence staining and flow cytometry analysis were used to assay the effects of Fn14 on the survival ability and apoptosis of SMMC7721 cells treated by TRAIL.Furthermore,an inhibitor of NF-κB activity was used to determine whether the effects of Fn14 on the survive and apoptosis were dependent on the activation of NF-κB.The results showed that overexpression of Fn14 prompts cellular survive and resists apoptosis induced by TRAIL.Meanwhile,increased expression of Fn14 results in translocation of p65 subunit of NF-κB to the nucleus from cytoplasm.Furthermore,increased survive and resisted apoptosis of cells induced by upregulated expression of Fn14 was dependent on the activation of NF-κB.The results implied that Fn14 may be potential marker of diagnosis and prognosis and serve as a target for therapy of liver cancer.
引文
1.Fujimori M,Tokino T,Hino O,Kitagawa T,Imamura T,Okamoto E,Mitsunobu M,Ishikawa T,Nakagama H,Harada H.Allelotype study of primary hepatocellular carcinoma.Cancer Res 1991;51:89-93.
2.Okuda K.Hepatocellular carcinoma.J Hepatol 2000;32:225-37.
3.Bosch FX,Ribes J,Diaz M,Clerics R.Primary liver cancer:worldwide incidence and trends.Gastroenterology 2004;127:S5-16.
4.Wands JR.Prevention of hepatocellular carcinoma.New Engl J Med 2004;351:1567-70.
5.Yamamoto J,Kosuge T,Yakayama T,et al.Recurrence of hepatocellular carcinoma after surgery.Br J Surg 1996;83(9):1219-22.
6.Chen XP,Qiu FZ,Wu ZD,et al.Long-term outcome of resection of large hepatocellular carcinoma.Br J Surg 2006;93(5):600-6.
7.Coleman WB.Mechanisms of human hepatocarcinogenesis.Curr Mol Med 2003;3:573-88.
8.Nagasue N,Kohno H,Chang YC,et al.Liver resection for hepatocellular carcinoma.Results of 229 consecutive patients during 11 years.Ann Surg 1993;217:375-384.
9.Bruix J,Boix L,Sala M,Llovet JM.Focus on hepatocellular carcinoma.Cancer Cell 2004;5:215-9.
10.Buendia MA.Genetics of hepatocellular carcinoma.Semin Cancer Biol 2000;10:185-200.
11.Thorgeirsson SS,Grisham JW.Molecular pathogenesis of human hepatocellular carcinoma.Nat Genet 2002;31:339-46.
12.Laurent-Puig P,Zucman-Rossi J.Genetics of hepatocellular tumors.Oncogene 2006;25:3778-86.
13.Farazi PA,Depinho RA.Hepatocellular carcinoma pathogenesis:from genes to environment.Nat Rev Cancer 2006;6:674-87.
14.Feitelson MA,Sun B,Satiroglu Tufan NL,et al.Genetic mechanisms of hepatocarcinogenesis.Oncogene 2002;21:2593-604.
15.Iizuka Net al.Molecular signature in three types of hepatocellular carcinoma with different viral origin by oligonucleotide microarray.Int.J.Oncol 2004;24:565-74.
16.Zhang LH,Ji JF.Molecular profiling of hepatocellular carcinomas by eDNA microarray.World J.Gastroenterol 2005;ll:463-8.Chen X,Cheung ST,So S,et al.Gene expression patterns in human liver cancers.Mol B iol Cell 2002;13:1929-1939.
17.Kim BY,Lee JG,Park S,et al.Feature genes of hepatitis B virus-positive hepatocellular carcinoma,established by its molecular discrimination approach using prediction analysis of microarray.Biochim Biophys Acta 2004;1739:50-61.
18.Neo SY,Leow CK,Vega VB,et al.Identification of discriminators of hepatoma by gene expression profiling using a minimal dataset approach.Hepatology 2004;39:944-953.
19.Xu XR,Huang J,Xu ZG,et al.Insight into hepatocellular carcinogenesis at transcriptome level by comparing gene expression profiles of hepatocellular carcinoma with those of corresponding noncancerous liver. Proc Natl Acad Sci USA 2001;98:15089-15094.
20. Anders RA, Yerian LM, Tretiakova M, et al. cDNA microarray analysis of macroregenerative and dysplastic nodules in end-stage hepatitis C virus-induced cirrhosis. Am J Pathol 2003;162:991-1000.
21. Delpuech O, Trabut JB, Carnot F, et al. Identification, using cDNA macroarray analysis, of distinct gene expression profiles associated with pathological and virological features of hepatocellular carcinoma. Oncogene 2002;21:2926-2937.
22. Iizuka N, Oka M, Yamada-Okabe H, et al. Oligonucleotide microarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection. Lancet 2003;361:923-929.
23. Lee JS, Thorgeirsson SS. Functional and genomic implications of global gene expression profiles in cell lines from human hepatocellular cancer. Hepatology 2002;35:1134- 1143.
24. Okabe H, Satoh S, Kato T, et al. Genome-wide analysis of gene expression in human hepatocellular carcinomas using cDNA microarray: identification of genes involved in viral carcinogenesis and tumor progression. Cancer Res 2001 ;61: 2129-213 7.
25. Paradis V, Bieche I, Dargere D, et al. Molecular profiling of hepatocellular carcinomas (HCC) using a large-scale realtime RT-PCR approach: determination of a molecular diagnostic index. Am J Pathol 2003;163:733-741.
26. Smith MW, Yue ZN, Korth MJ, et al. Hepatitis C virus and liver disease: global transcriptional profiling and identification of potential markers. Hepatology 2003;38:1458-1467.
27. Smith MW, Yue ZN, Geiss GK, et al. Identification of novel tumor markers in hepatitis C virus-associated hepatocellular carcinoma. Cancer Res 2003;63:859-864.
28. Ye QH, Qin LX, Forgues M, et al. Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med 2003 ;9:416-423.
29. Liang P, Averboukh L, Keyomarsi K, Sager R and Pardee AB: Differential display and cloning of messenger RNAs from human breast cancer versus mammary epithelial cells. Cancer Res 1992; 52: 6966-6968.
30. Vasmatzis G, Essand M, Brinkmann U, Lee B and Pastan I: Discovery of three genes specifically expressed in human prostate by expressed sequence tag database analysis. Proc Natl Acad Sci USA 1998; 95: 300-304.
31. Jiang H, Kang DC, Alexandre D and Fisher PB: RaSH, a rapid subtraction hybridization approach for identifying and cloning differentially expressed genes. Proc Natl Acad Sci USA 2000; 97: 12684-12689.
32. Velculescu VE, Zhang L, Vogelstein B and Kinzler KW: Serial analysis of gene expression. Science 270: 484-487, 1995.
33. Schena M, Shalon D, Davis RW and Brown PO: Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science 270: 467-470,1995.
34. Diatchenko L, Lau YF, Campbell AP, Chenchik A, Moqadam F, Huang B, Lukyanov S, Lukyanov K, Gurskaya N, Sverdlov ED and Siebert PD: Suppression subtractive hybridization: a method for generation differentially regulated or tissue-specific cDNA probes and libraries. Proc Natl Acad Sci USA 93: 6025-6030, 1996.
35.Yang GP,Ross DT,Kuang WW,Brown PO and Weigel RJ:Combining SSH and cDNA microarray for rapid identification of differentially expressed genes.Nuceic Acids Res 27:1517-1523,1999.
36.Villaret DB,Wang T,Dillon D,Xu J,Sivam D,Cheever MA and Reed SG:Identification of genes overexpressed in head and neck squamous cell carcinoma using a combination of complementary DNA subtraction and microarray analysis.Laryngoscope 110:374-381,2000.
37.Kojiro M,Roskams T.Early hepatocellular carcinoma and dysplastic nodules.Semin Liver Dis 2005;25:133-142.
38.Grisham JW.Interspecies comparison of liver carcinogenesis:implications for cancer risk assessment.Carcinogenesis 1997;18:59-81.
39.Llovet JM,Burroughs A,Bruix J.Hepatocellular carcinoma.Lancet 2003;362:1907-1917.
40.Van Dyke T,Jacks T.Cancer modeling in the moderu era:progress and challenges.Cell 2002;108:135-144.
41.Klausner RD.Studying cancer in the mouse.Oncogene 1999;18:5249-5252
42.Kojiro M.Histopathology of liver cancers.Best Pract Res Clin Gastroenterol 2005;19:39-62.
43.Yhshijih,Yoshiij,Ikenakay,et al.Inhibition of renninangtotensm system attenuates liber enzyme-altered preneoplastic lesions and fibrosis development in rats.J Hepatal 2002;37(1):22-30.
44.程延安,袁利超,等.间断小剂量DEN诱发大鼠肝癌模型研究.肿瘤防治杂志2005;12(11):806-808.
1.Shuda M,Kondoh N,Tanaka K,Ryo A,Wakatsuki T,Hada A,Goseki N,Igari T,Hatsuse K,Aihara T,Horiuchi S,Shichita M,Yamamoto N and Yamamoto M:Enhanced expression of translation factor mRNAs in hepatocellular carcinoma.Anticancer Res 2000;20:2489-2494.
2.Tarantul VZ,Nikolaev AI,Martynenko A,Hannig H,Hunsmann G and Bodemer W:Differential gene expression in B-cell non-Hodgkin's lymphoma of SIV-infected monkey.AIDS Res Hum Retroviruses2000;16:173-179.
3.Van Duin M,van Marion R,Vissers K,et ah High-resolution array comparative genomic hybridization of chromosome arm 8q:evaluation of genetic progression markers for prostate cancer.Genes Chromosomes Cancer 2005;44:438-449.
4.Leite-Browning ML,McCawley L J,Jahnen-Dechent W,King LE Jr,Matrisian LM and Ochieng J:Alpha 2-HS glycoprotein(fetuin-A)modulates murine skin tumorigenesis.Int J Oncol 2004;25:319-324.
5.Ribom D,westman-Brinkmalm A,Smits A and Davidsson P:Elevated levels of alpha-2-Heremans-Schmid glycoprotein in CSF of patients with low-grade gliomas.Tumour Biol 2003;24:94-99.
6.Morioka Y,Ikeda M,Saiga A,Fujii N,Ishimoto Y,Arita H and Hanasaki K:Potential role of group X secretory phospholipase A(2)in cyclooxygenase-2-dependent PGE(2)formation during colon tumorigenesis.FEBS Lett 2000;487:262-266.
7.Park JW,Park JE,Lee JA,Lee CW and Kim CM:Cyclooxygenase- 2(COX-2)is directly involved but not decisive in proliferation of human hepatocellular carcinoma cells.J Cancer Res Clin Oncol 2006;132:184-192.
8.Zhao QT,Yue SQ,Cui Z,Wang Q,Cui X,Zhai HH,Zhang LH and Dou KF:Potential involvement of the cyclooxygenase-2 pathway in hepatocellular carcinoma-associated angiogenesis.Life Sci 2007;80:484-492.
9.Mosser DD and Morimoto RI:Molecular chaperones and the stress of oncogenesis.Oncogene 2004;23:2907-2918.
10.Jolly C and Morimoto RI:Role of the heat shock response and molecular chaperones in oncogenesis and cell death.J Natl Cancer Inst 2000;92:1564-1572.
11.Malusecka E,Zborek A,Krzyzowska-Gruca S and Krawczyk Z:Expression of heat shock proteins HSP70 and HSP27 in primary non-small cell lung carcinomas.An immunohistochemical study.Anticancer Res 2001;21:1015-1021.
12.Cornford PA,Dodson AR,Parsons KF,Desmond AD,Woolfenden A,Fordham M,Neoptolemos JP,Ke Y and Foster CS:Heat shock protein expression independently predicts clinical outcome in prostate cancer.Cancer Res 2000;60:7099-7105.
13. Rohde M, Daugaard M, Jensen MH, Helin K, Nylandsted J and Jaattela M: Members of the heat-shock protein 70 family promote cancer cell growth by distinct mechanisms. Genes Dev 2005; 19: 570-582.
14. Thornalley PJ: Protecting the genome: defence against nucleotide glycation and emerging role of glyoxalase I overexpression in multidrug resistance in cancer chemotherapy. Biochem Soc Trans 2003; 31: 1372-1377.
15. Filipenko NR, MacLeod TJ, Yoon CS and Waisman DM: Annexin A2 is a novel RNA-binding protein. J Biol Chem 2004; 279: 8723-8731.
16. Gilmore WS, Olwill S, McGlynn H and Alexander HD: Annexin A2 expression during cellular differentiation in myeloid cell lines. Biochem Soc Trans 2004; 32:1122-1123.
17. Tatenhorst L, Rescher U, Gerke V and Paulus W: Knockdown of annexin 2 decreases migration of human glioma cells in vitro. Neuropathol Appl Neurobiol 2006; 32: 271-277.
18. Yoon SY, Kim JM, Oh JH, Jeon YJ, Lee DS, Kim JH, Choi JY, Ahn BM, Kim S, Yoo HS, Kim YS and Kim NS: Gene expression profiling of human HBV- and/or HCV-associated hepatocellular carcinoma cells using expressed sequence tags. Int J Oncol 2006; 29: 315-327.
19. Wang AG, Yoon SY, Oh JH, Jeon YJ, Kim M, Kim JM, Byun SS, Yang JO, Kim JH, Kim DG, Yeom YI, Yoo HS, Kim YS and Kim NS: Identification of intrahepatic cholangiocarcinoma related genes by comparison with normal liver tissues using expressed sequence tags. Biochem Biophys Res Commun 2006; 345:1022-1032.
20. Essner JJ, Chen E and Ekker SC: Syndecan-2. Int J Biochem Cell Biol 2006; 38: 152-156.
21. Kobe B and Deisenhofer J: The leucine-rich repeat: a versatile binding motif. Trends Biochem Sci 1994; 19: 415-421.
22. Kobe B and Deisenhofer J: A structural basis of the interactions between leucine-rich repeats and protein ligands. Nature 1995; 374: 183-186.
23. Bredel M and Pollack IF: The p21-Ras signal transduction pathway and growth regulation in human high-grade gliomas. Brain Res Brain Res Rev 1999; 29: 232-249.
24. Berry-Kravis E and Ciurlionis R: Overexpression of fragile X gene (FMR-1) transcripts increases cAMP production in neural cells. J Neurosci Res 1998; 51: 41-48.
25. Woutersen RA, Appelman LM, van Garderen-Hoetmer A and Feron VJ: Inhalation toxicity of acetaldehyde in rats. III. Carcinogenicity study. Toxicology 1986; 41: 213-231.
26. Caso G, McNurlan MA, McMillan ND, Eremin O and Garlick PJ: Tumour cell growth in culture: dependence on arginine. Clin Sci 2004; 107: 371-379.
27. Yokoyama Y, Kuramitsu Y, Takashima M, Iizuka N, Toda T, Terai S, Sakaida I, Oka M, Nakamura K and Okita K: Proteomic profiling of proteins decreased in hepatocellular carcinoma from patients infected with hepatitis C virus. Proteomics 2004; 4: 2111-2116.
28. Rodriguez-Antona C and Ingelman-Sundberg M: Cytochrome P450 pharmacogenetics and cancer. Oncogene 2006; 25: 1679-1691.
29. Chen J, Xu J, Ying K, Cao G, Hu G, Wang L, Luo C, Lou M, Mao Y, Xie Y and Lu Y: Molecular cloning and characterization of a novel human BTB domain-containing gene, BTBD10, which is down-regulated in glioma. Gene 2004; 340:61-69.
1. Thorgeirsson SS and Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 2002;31, 339 - 346.
2. Lee JS, Chu IS, Heo J, Calvisi DF, Sun Z, Roskams T, Durnez A., Demetris AJ, and Thorgeirsson SS. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology 2004; 40, 667 - 676.
3. Feitelson MA, Pan J, and Lian Z. Early molecular and genetic determinants of primary liver malignancy. Surg Clin North Am 2004; 84,339 - 354.
4. Umeda T, Hino O. Molecular aspects of human hepatocarcinogenesis mediated by inflammation: From hypercarcinogenic state to normo- or hypo carcinogenic state. Oncology 2002; 62 Suppl 138-42.
5. Garber K. Energy boost, the Warburg Effect returns in a new theory of cancer. J Natl Cancer Inst 2004; 96: 1805-6.
6. Young CD, Anderson SM. Sugar and fat - that's where it's at: metabolic changes in tumors.Breast Cancer Res. 2008;10(1):202.
7. Ramanathan A, Wang C, Schreiber SL. Perturbational profiling of a cell-line model of tumorigenesis by using metabolic measurements. Proc Natl Acad Sci USA 2005;102:5992-5997.
8. Pelicano H, Martin DS, Xu RH, Huang P. Glycolysis inhibition for anticancer treatment. Oncogene 2006; 25:4633-4646.
9. Wittig R, Coy JF. The Role of Glucose Metabolism and Glucose-Associated Signalling in Cancer. Perspectives in Medicinal Chemistry 2007; 1:64-82.
10. Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, Zhuang H, Cinalli RM, Alavi A, Rudin CM, Thompson CB. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 2004; 64:3892-3899.
11. Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer 2004; 4:891-899.
12. Stern R, Shuster S, Neudecker BA, Formby B: Lactate stimulates fibroblast expression of hyaluronan and CD44: the Warburg effect revisited. Exp Cell Res 2002; 276:24-31.
13. Walenta S, Wetterling M, Lehrke M, Schwickert G, Sundf0r K, Rofstad EK, Mueller-Klieser W. High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res 2000; 60:916-921.
14. Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, Gottfried E, Schwarz S, Rothe G, Hoves S, Renner K, Timischl B, Mackensen A, Kunz-Schughart L, Andreesen R, Krause SW, Kreutz M. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 2007;109:3812-3819.
15. Philips BJ, Dhir R, Hutzley J, Sen M, Kelavkar UP. Polyunsaturated fatty acid metabolizing 15-Lipoxygenase-1 (15-LO-1) expression in normal and tumorigenic human bladder tissues. Appl Immunohistochem Mol Morphol. 2008;16(2):159-64.
16. Ntambi JM, Miyazaki M, Dobrzyn A.Regulation of stearoyl-CoA desaturase expression. Lipids. 2004;39(11):1061-5.
17. Miyazaki M, Dobrzyn A, Elias PM, Ntambi JM. Stearoyl-CoA desaturase-2 gene expression is required for lipid synthesis during early skin and liver development. Proc Natl Acad Sci USA. 2005;102(35):12501-6.
18. Christianson JL, Nicoloro S, Straubhaar J, Czech MP. Stearoyl-CoA desaturase 2 is required for peroxisome proliferator-activated receptor gamma expression and adipogenesis in cultured 3T3-L1 cells. J Biol Chem. 2008; 283(5):2906-16.
19. Uma RS, Naresh KN, D'Cruz AK, Mulherkar R, Borges AM. Metastasis of squamous cell carcinoma of the oral tongue is associated with down-regulation of epidermal fatty acid binding protein (E-FABP). Oral Oncol. 2007; 43(1):27-32.
20. Ordovas JM. Identification of a functional polymorphism at the adipose fatty acid binding protein gene (FABP4) and demonstration of its association with cardiovascular disease: a path to follow. Nutr Rev. 2007; 65(3): 130-4.
21. Gillilan RE, Ayers SD, Noy N. Structural basis for activation of fatty acid-binding protein 4. J Mol Biol. 2007; 372(5): 1246-60.
22. Rodriguez-Antona C, Ingelman-Sundberg M. Cytochrome P450 pharmacogenetics and cancer. Oncogene. 2006; 25(11): 1679-91.
23. Bergheim I, Wolfgarten E, Bollschweiler E, Holscher AH, Bode C, Parlesak A.Cytochrome P450 levels are altered in patients with esophageal squamous-cell carcinoma. World J Gastroenterol. 2007;13(7):997-1002.
24. McFadyen MC, Murray GI. Cytochrome P450 1B1: a novel anticancer therapeutic target. Future Oncol. 2005;l(2):259-63.
25. Vaclavikova R, Hubackova M, Stribrna-Sarmanova J, Kodet R, Mrhalova M, Novotny J, Gut I, Soucek P.RNA expression of cytochrome P450 in breast cancer patients. Anticancer Res. 2007;27(6C):4443-50.
26. Nebert DW, Dalton TP. The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis. Nat Rev Cancer. 2006;6(12):947-60.
27. Scibior D, Skrzycki M, Podsiad M, Czeczot H. Glutathione level and glutathione-dependent enzyme activities in blood serum of patients with gastrointestinal tract tumors. Clin Biochem. 2008 Mar 20,E pub ahead of print.
28. Pljesa-Ercegovac M, Mimic-Oka J, Dragicevic D, Savic-Radojevic A, Opacic M, Pljesa S, Radosavljevic R, Simic T. Altered antioxidant capacity in human renal cell carcinoma: role of glutathione associated enzymes.Urol Oncol. 2008; 26(2):175-81.
29. Naiki-Ito A, Asamoto M, Hokaiwado N, Takahashi S, Yamashita H, Tsuda H, Ogawa K, Shirai T. Gpx2 is an overexpressed gene in rat breast cancers induced by three different chemical carcinogens. Cancer Res. 2007;67(23): 11353-8.
30. Kipp A, Banning A, Brigelius-Flohe R. Activation of the glutathione peroxidase 2 (GPx2) promoter by beta-catenin. Biol Chem. 2007; 388(10):1027-33.
31. Farber E. Experimental induction of hepatocellular carcinoma as a paradigm for carcinogenesis. Clin Physiol Biochem1987; 5:152 - 159.
32. Hendrich S, Campbell HA, and Pitot HC. Quantitative stereological evaluation of four histochemical markers of altered foci in multistage hepatocarcinogenesis in the rat. Carcinogenesis 1987; 8:1245 - 1250.
33. Higashi K, Hiai H, Higashi T, and Muramatsu M . Regulatory mechanism of glutathione S-transferase P-form during chemical hepatocarcinogenesis: old wine in a new bottle. Cancer Lett 2004; 209:155-163.
34. Hayes JD and Pulford DJ . The glutathione S-transferase supergene family: regulation of GSTand the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol 1995; 30: 445 - 600.
35. Lu SC. Regulation of hepatic glutathione synthesis: current concepts and controversies. FASEB J 1999;13: 1169-1183.
36. Huang ZZ, Chen C, Zeng Z, Yang H, Oh J, Chen L, and Lu SC. Mechanism and significance of increased glutathione level in human hepatocellular carcinoma and liver regeneration. FASEB J 2001; 15: 19 - 21.
37. Schwarz KB, Kew M, Klein A, Abrams RA, Sitzmann J, Jones L, Sharma S, Britton RS, Di Bisceglie AM, and Groopman J. Increased hepatic oxidative DNA damage in patients with hepatocellular carcinoma. Dig Dis Sci 2001; 46:2173 - 2178.
38. Jungst C, Cheng B, Gehrke R, Schmitz V, Nischalke HD, Ramakers J, Schramel P, Schirmacher P, Sauerbruch T, and Caselmann WH. Oxidative damage is increased in human liver tissue adjacent to hepatocellular carcinoma. Hepatology 2004; 39: 1663 -1672.
39. Baumann C, Davies B, Peters M, Kaufmann-Reiche U, Lessl M, Theuring F. AKR1B7 (mouse vas deferens protein) is dispensable for mouse development and reproductive success. Reproduction. 2007;134(1):97-109.
40. Jia G, Takahashi R, Zhang Z, Tsuji Y, Sone H. Aldo-keto reductase 1 family B7 is the gene induced in response to oxidative stress in the livers of Long-Evans Cinnamon rats. Int J Oncol. 2006; 29(4):829-38.
41. Dewa Y, Nishimura J, Muguruma M, Jin M, Saegusa Y, Okamura T, Tasaki M, Umemura T, Mitsumori K.beta-Naphthoflavone enhances oxidative stress responses and the induction of preneoplastic lesions in a diethylnitrosamine-initiated hepatocarcinogenesis model in partially hepatectomized rats. Toxicology. 2008; 244(2-3): 179-89.
42. Ushio-Fukai M, Nakamura Y.Reactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy. Cancer Lett. 2008 Apr 9 [Epub ahead of print]
43. Lee JK, Edderkaoui M, Truong P, Ohno I, Jang KT, Berti A, Pandol SJ, Gukovskaya AS. NADPH oxidase promotes pancreatic cancer cell survival via inhibiting JAK2 dephosphorylation by tyrosine phosphatases. Gastroenterology. 2007; 133(5): 1637-48.
44. Xia C, Meng Q, Liu LZ, Rojanasakul Y, Wang XR, Jiang BH. Reactive oxygen species regulate angiogenesis and tumor growth through vascular endothelial growth factor.Cancer Res. 2007;67(22): 10823-30.
45. Masamune A, Watanabe T, Kikuta K, Satoh K, Shimosegawa T. NADPH oxidase plays a crucial role in the activation of pancreatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2008;294(1):G99-G108.
46. Hendriks WJ, Elson A, Harroch S, Stoker AW. Protein tyrosine phosphatases: functional inferences from mouse models and human diseases. FEBS J. 2008;275(5):816-30.
47. Xing Y, Li Z, Chen Y, Stock JB, Jeffrey PD, Shi Y. Structural mechanism of demethylation and inactivation of protein phosphatase 2A. Cell. 2008;133(1):154-63.
48. Guenin S, Schwartz L, Morvan D, Steyaert JM, Poignet A, Madelmont JC, Demidem A. PP2A activity is controlled by methylation and regulates oncoprotein expression in melanoma cells: a mechanism which participates in growth inhibition induced by chloroethylnitrosourea treatment. Int J Oncol. 2008; 32(1):49-57.
49. Kuo YC, Huang KY, Yang CH, Yang YS, Lee WY, Chiang CW. Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt. J Biol Chem. 2008; 283(4): 1882-92.
50. Junttila MR, Westermarck J. Mechanisms of MYC stabilization in human malignancies. Cell Cycle. 2008; 7(5):592-6.
51. Li X, Chen D, Yin S, Meng Y, Yang H, Landis-Piwowar KR, Li Y, Sarkar FH, Reddy GP, Dou QP, Sheng S. Maspin augments proteasome inhibitor-induced apoptosis in prostate cancer cells J Cell Physiol. 2007; 212(2):298-306.
52. Liu N, Wang Y, Ashton-Rickardt PG. Serine protease inhibitor 2A inhibits caspase-independent cell death. FEBS Lett. 2004; 569(1-3):49-53.
53. Kashima K, Ohike N, Mukai S, Sato M, Takahashi M, Morohoshi T. Expression of the tumor suppressor gene maspin and its significance in intraductal papillary mucinous neoplasms of the pancreas. Hepatobiliary Pancreat Dis Int. 2008; 7(1):86-90.
54. Takahashi H, Sawai H, Funahashi H, Matsuo Y, Yasuda A, Ochi N, Sato M, Okada Y, Takeyama H.Antiproteases in preventing the invasive potential of pancreatic cancer cells. JOP. 2007; 8(4 Suppl):501-8.
55. Hayes MJ, Longbottom RE, Evans MA, Moss SE. Annexinopathies. Subcell Biochem. 2007;45:l-28.
56. Brichory FM, Misek DE, Yim AM, et al. An immune response manifested by the common occurrence of Annexin I and Annexin II autoantibodies and high circulating levels of IL-6 in lung cancer. Proc Natl Acad Sci USA 2001; 98:9824-9829.
57. Emoto K, Yamada Y, Sawada H, et al. Annexin II overexpression correlates with stromal tenascin-C overexpression: a prognostic marker in colorectal carcinoma. Cancer 2001; 92:1419-1426.
58. Morel E, Gruenberg J. The p11/S100A10 light chain of annexin A2 is dispensable for annexin A2 association to endosomes and functions in endosomal transport. PLoS ONE. 2007 Oct 31;2(10):e1118.
59. Ito Y, Arai K, Nozawa R, Yoshida H, Higashiyama T, Takamura Y, Miya A, Kobayashi K, Kuma K, Miyauchi A. S100A10 expression in thyroid neoplasms originating from the follicular epithelium: contribution to the aggressive characteristic of anaplastic carcinoma. Anticancer Res. 2007; 27(4C):2679-83.
60. Zhang Y, Zhou ZH, Bugge TH, Wahl LM. Urokinase-type plasminogen activator stimulation of monocyte matrix metalloproteinase-1 production is mediated by plasmin-dependent signaling through annexin A2 and inhibited by inactive plasmin. J Immunol. 2007;179(5):3297-304.
61. Full en DR, Garrisi AJ, Sanders D, Thomas D. Expression of S100A6 protein in a broad spectrum of cutaneous tumors using tissue microarrays. J Cutan Pathol. 2008 Jan 14 [Epub ahead of print]
62. Ghavami S, Rashedi I, Dattilo BM, Eshraghi M, Chazin WJ, Hashemi M, Wesselborg S, Kerkhoff C, Los M. S100A8/A9 at low concentration promotes tumor cell growth via RAGE ligation and MAP kinase-dependent pathway. J Leukoc Biol. 2008 Mar 13 [Epub ahead of print]
63. Kim HJ, Kim JB, Lee KM, Shin I, Han W, Ko E, Bae JY, Noh DY. Isolation of CD24(high) and CD24(low/-) cells from MCF-7: CD24 expression is positively related with proliferation, adhesion and invasion in MCF-7. Cancer Lett. 2007; 258(1):98-108.
64. Sagiv E, Memeo L, Karin A, Kazanov D, Jacob-Hirsch J, Mansukhani M, Rechavi G, Hibshoosh H, Arber N. CD24 is a new oncogene, early at the multistep process of colorectal cancer carcinogenesis. Gastroenterology. 2006;131(2):630-9.
65. Chou YY, Jeng YM, Lee TT, Hu FC, Kao HL, Lin WC, Lai PL, Hu RH, Yuan RH. Cytoplasmic CD24 expression is a novel prognostic factor in diffuse-type gastric adenocarcinoma. Ann Surg Oncol. 2007;14(10):2748-58.
66. Kwon GY, Ha H, Ahn G, Park SY, Huh SJ, Park W. Role of CD24 protein in predicting metastatic potential of uterine cervical squamous cell carcinoma in patients treated with radiotherapy. Int J Radiat Oncol Biol Phys. 2007; 69(4): 1150-6.
67. Agrawal S, Kuvshinoff BW, Khoury T, Yu J, Javle MM, LeVea C, Groth J, Coignet LJ, Gibbs JF. CD24 expression is an independent prognostic marker in cholangiocarcinoma. J Gastrointest Surg. 2007; 11(4):445-51.
68. Looi LM, Cheah PL, Zhao W, Ng MH, Yip CH. CD44 expression and axillary lymph node metastasis in infiltrating ductal carcinoma of the breast. Malays J Pathol. 2006; 28(2):83-6.
69. Lee SM, Lee KE, Chang HJ, Choi MY, Cho MS, Min SK, Lee HK, Mun YC, Nam EM, Seong CM, Lee SN.Ann Surg Oncol. Prognostic significance of CD44s expression in biliary tract cancers. 2008; 15(4): 1155-60.
70. Lim SD, Young AN, Paner GP, Amin MB. Prognostic role of CD44 cell adhesion molecule expression in primary and metastatic renal cell carcinoma: a clinicopathologic study of 125 cases. Virchows Arch. 2008; 452(1):49-55.
71. Ouhtit A, Abd Elmageed ZY, Abdraboh ME, Lioe TF, Raj MH. In vivo evidence for the role of CD44s in promoting breast cancer metastasis to the liver. Am J Pathol. 2007;171(6):2033-9.
72. Stein R, Mattes MJ, Cardillo TM, Hansen HJ, Chang CH, Burton J, Govindan S, Goldenberg DM.Clin Cancer Res. CD74: a new candidate target for the immunotherapy of B-cell neoplasms. 2007;13(18 Pt 2):5556s-5563s.
73. Shi X, Leng L, Wang T, Wang W, Du X, Li J, McDonald C, Chen Z, Murphy JW, Lolis E, Noble P, Knudson W, Bucala R. CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex. Immunity. 2006; 25(4):595-606.
74. Beswick EJ, Pinchuk IV, Suarez G, Sierra JC, Reyes VE. Helicobacter pylori CagA-dependent macrophage migration inhibitory factor produced by gastric epithelial cells binds to CD74 and stimulates procarcinogenic events. J Immunol. 2006;176(11):6794-801.
75. Koide N, Yamada T, Shibata R, Mori T, Fukuma M, Yamazaki K, Aiura K, Shimazu M, Hirohashi S, Nimura Y, Sakamoto M. Establishment of perineural invasion models and analysis of gene expression revealed an invariant chain (CD74) as a possible molecule involved in perineural invasion in pancreatic cancer. Clin Cancer Res. 2006;12(8):2419-26.
76. Hahn WC, Weinberg RA. Rules for making human tumor cells. N Engl J Med 2002;347:1593-1603.; Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nature Med 2004; 10:789-799.
77. Duffy MJ. The biochemistry of metastasis. Adv Clin Chem 1996;32:135-166.
78. Poste G, Fidler IJ. The pathogenesis of cancer metastasis. Nature 1980;283:139-146.
79. Bernards R, Weinberg RA. A progression puzzle. Nature 2002;418:823.
80. Duffy MJ, Kelly ZD, Culhane AC, O'Brien A, Gallagher WM. DNA microarray-based gene expression profiling in cancer: aiding cancer diagnosis, assessing prognosis and predicting response to therapy. Curr Pharmacogenomics 2005 ;3: 289-304.
81. Chambers AF, Tuck AB. Ras-responsive genes and tumor metastasis. Crit Rev Oncog 1993;4:95-114.
82. Yu D, Wang SS, Dulski KM, Tsai CM, Nicolson GL, Hung MC. c-erbB-2/neu overexpression enhances metastatic potential of human lung cancer cells by induction of metastasis-associated properties. Cancer Res 1994;54:3260—3266.
83. Myoui A, Nishimura R, Williams PJ, Hiraga T, Tamura D, Michigami T, et al. C-SRC tyrosine kinase activity is associated with tumor colonization in bone and lung in an animal model of human breast cancer metastasis. Cancer Res 2003;63:5028-5033.
84. Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nature Rev Cancer 2002;2:161-174.
85. Duffy MJ. The urokinase plasminogen activator system: role in malignancy. Curr Pharm Des2004;10:39-49.
86. Parekh S, Prive G, Melnick A. Therapeutic targeting of the Bcl6 oncogene for diffuse large B-cell lymphomas. Leuk Lymphoma. 2008; 49(5):874-82.
87. Perez-Rosado A, Artiga M, Vargiu P, Sanchez-Aguilera A, Alvarez-Barrientos A, Piris M. BCL6 represses NFkappaB activity in diffuse large B-cell lymphomas. J Pathol. 2008;214(4):498-507.
88. Zhang J, Chen S, Zhang W, Zhang J, Liu X, Shi H, Che H, Wang W, Li F, Yao L. Human differentiation-related gene NDRG1 is a Myc downstream-regulated gene that is repressed by Myc on the core promoter region. Gene. 2008 Mar 12 [Epub ahead of print]
89. Kovacevic Z, Richardson DR. The metastasis suppressor, Ndrg-1: a new ally in the fight against cancer. Carcinogenesis. 2006; 27(12):2355-66.
90. Zhang J, Li F, Liu X, Shen L, Liu J, Su J, Zhang W, Deng Y, Wang L, Liu N, Han W, Zhang J, Ji S, Yang A, Han H, Yao L.The repression of human differentiation-related gene NDRG2 expression by Myc via Miz-1-dependent interaction with the NDRG2 core promoter. J Biol Chem. 2006; 281(51):39159-68.
91. Wang L, Liu N, Yao L, Li F, Zhang J, Deng Y, Liu J, Ji S, Yang A, Han H, Zhang Y, Zhang J, Han W, Liu X. NDRG2 is a new HIF-1 target gene necessary for hypoxia-induced apoptosis in A549 cells. Cell Physiol Biochem. 2008;21(1-3):239-50.
92. Choi SC, Yoon SR, Park YP, Song EY, Kim JW, Kim WH, Yang Y, Lim JS, Lee HG.Expression of NDRG2 is related to tumor progression and survival of gastric cancer patients through Fas-mediated cell death. Exp Mol Med. 2007; 39(6):705-14.
93. Lorentzen A, Vogel LK, Lewinsky RH, Saeb0 M, Skjelbred CF, Godiksen S, Hoff G, Tveit KM, Lothe IM, Ikdahl T, Kure EH, Mitchelmore C. Expression of NDRG2 is down-regulated in high-risk adenomas and colorectal carcinoma. BMC Cancer. 2007; 7:192.
94. Park Y, Shon SK, Kim A, Kim KI, Yang Y, Cho DH, Lee MS, Lim JS.SOCS1 induced by NDRG2 expression negatively regulates STAT3 activation in breast cancer cells. Biochem Biophys Res Commun. 2007; 363(2):361-7.
95. Hsieh YS, Lee YL, Yang SF, Yang JS, Chen W, Chen SC, Shih CM. Association of EcoRI polymorphism of the metastasis-suppressor gene NME1 with susceptibility to and severity of non-small cell lung cancer. Lung Cancer. 2007; 58(2):191-5.
96. Sers C, Husmann K, Nazarenko I, Reich S, Wiechen K, Zhumabayeva B, Adhikari P, Schroder K, Gontarewicz A, Schafer R.The class II tumour suppressor gene H-REV107-1 is a target of interferon-regulatory factor-1 and is involved in IFNgamma-induced cell death in human ovarian carcinoma cells. Oncogene. 2002 Apr 25;21(18):2829-39.
97. Siegrist S, Feral C, Chami M, Solhonne B, Mattei MG, Rajpert-De Meyts E, Guellaen G, Bulle F. hH-RevlO7, a class II tumor suppressor gene, is expressed by post-meiotic testicular germ cells and CIS cells but not by human testicular germ cell tumors. Oncogene. 2001;20(37):5155-63.
98. Nazarenko I, Schafer R, Sers C. Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells. J Cell Sci. 2007;120(Pt 8):1393-404.
99. R.A. Cairns, R. Khokha, R.P. Hill, Molecular mechanisms of tumor invasion and metastasis: an integrated view. Curr Mol Med2003; 3: 659-671.
100. L.M. Coussens, Z.Werb, Inflammation and cancer. Nature 2002; 420: 860-867.
101.Grigioni WF, Garbisa S, D'Errico A, et al. Evaluation of hepatocellular carcinoma aggressiveness by a panel of extracellular matrix antigens. Am J Pathol 1991 ;138: 647-54.
102. Torimura T, Ueno T, Inuzuka S, et al. The extracellular matrix in hepatocellular carcinoma shows different localization patterns depending on the differentiation and the histological pattern of tumors: immunohistochemical analysis. J Hepatol 1994; 21:37-46.].
103. Bissell DM. Chronic liver injury, TGF-beta, and cancer. Exp Mol Med 2001;33:179-90.
104. Yoshiji H, Kuriyama S, Yoshii J, et al. Extracellular matrix remodeling may predominate over hepatocyte injury in hepatocellular carcinoma development. Oncol Rep 2003;10:957-62.
105. Carloni V, Romanelli RG, Mercurio AM, et al. Knockout of alpha6beta1-integrin expression reverses the transformed phenotype of hepatocarcinoma cells. Gastroenterology 1998;115:433-42.
106. Yang C, Zeisberg M, Lively JC, Nyberg P, Afdhal N, Kalluri R. Integrin alphalbetal and alpha2betal are the key regulators of hepatocarcinoma cell invasion across the fibrotic matrix microenvironment. Cancer Res 2003;63:8312—7.
107. Giannelli G, Bergamini C, Fransvea E, Marinosci F, Quaranta V, Antonaci S. Human hepatocellular carcinoma (HCC) cells require both alpha3beta1 integrin and matrix metalloproteinases activity for migration and invasion. Lab Invest 2001;81:613-27.
108. Fu BH, Wu ZZ, Dong C. Integrin beta1 mediates hepatocellular carcinoma cells chemotaxis to laminin. Hepatobiliary Pancreat Dis Int 2004;3:548-51.
109. Le Bail B, Faouzi S, Boussarie L, Balabaud C, Bioulac-Sage P, Rosenbaum J. Extracellular matrix composition and integrin expression in early hepatocarcinogenesis in human cirrhotic liver. J Pathol 1997;181:330-7.
110. Cariati M, Naderi A, Brown JP, Smalley MJ, Pinder SE, Caldas C, Purushotham AD.Alpha-6 integrin is necessary for the tumourigenicity of a stem cell-like subpopulation within the MCF7 breast cancer cell line. Int J Cancer. 2008;122(2):298-304.
111. Zhang H, Ozaki I, Mizuta T, et al. Transforming growth factor-beta1-induced apoptosis is blocked by beta1-integrin- mediated mitogen-activated protein kinase activation in human hepatoma cells. Cancer Sci 2004;95: 878-86.
112. Zhang H, Ozaki I, Mizuta T, et al. Beta1-integrin protects hepatoma cells from chemotherapy induced apoptosis via a mitogen-activated protein kinase dependent pathway. Cancer 2002;95:896-906.
113. Tian B, Li Y, Ji XN, et al. Basement membrane proteins play an active role in the invasive process of human hepatocellular carcinoma cells with high metastasis potential. J Cancer Res Clin Oncol 2005; 131:80-6.
114. Torbenson M, Wang J, Choti M, et al. Hepatocellular carcinomas show abnormal expression of fibronectin protein. Mod Pathol 2002; 15:826-30.
115. Coussens, L. M. and Werb, Z. Inflammation and cancer. Nature 2002; 420: 860-867.
116. Slaga TJ, Lichti U, Hennings H, Elgjo K, Yuspa SH. Effects of tumor promoters and steroidal anti-inflammatory agents on skin of newborn mice in vivo and in vitro. J Natl Cancer Inst 1978;60:425-31.
117. Jackson JR, Seed MP, Kircher CH, Willoughby DA, Winkler JD. The codependence of angiogenesis and chronic inflammation. FASEB J 1997;11:457—65.
118. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100:57-70.
1.Feng SL,Guo Y,Factor VM,etal.The Fnl4 immediate early response gene is induced during liver regeneration and highly expressed in both human and murine hepatocellular carcinomas.Am J Pathol,2000;156(4):1253-1261.
2.Tran NL,McDonough WS,Savitch BA,Fortin SP,Winkles JA,Symons M,Nakada M,Cunliffe HE,Hostetter G,Hoelzinger DB,Rennert JL,Michaelson JS,Burkly LC,Lipinski CA,Loflus JC,Mariani L,Berens ME.Increased Fibroblast Growth Factor-Inducible 14Expression Levels Promote Glioma Cell Invasion via Racl and Nuclear Factor-{kappa}B and Correlate with Poor Patient Outcome.Cancer Res.2006;66(19):9535-42.
3.Tran NL,McDonough WS,Savitch BA,Sawyer TF,Winkles JA,Berens ME.The tumor necrosis factor-like weak inducer of apoptosis(TWEAK)-fibroblast growth factor-inducible 14(Fnl4)signaling system regulates glioma cell survival via NFkappaB pathway activation and BCL-XL/BCL-W expression.J Biol Chem.2005;280(5):3483-92.
4.Lee JS,Thorgeirsson SS.Comparative and integrative functional genomics of HCC.Oncogene 2006;25:3801-9.
5.Yamagishi,N.,Miyakoshi,J.,and Takebe,H.Int.J.Radiat.Biol.1997;72,157-162.
6.Miyakoshi,J.,and Yagi,K.Br.J.Cancer 2000;82,28-33.
7.Ding,G.R.,Honda,N.,Nakahara,T.,Tian,F.,Yoshida,M.,Hirose,H.,and Miyakoshi,J.Radiat.Res.2003;160,232-237.
8.Ravi,R.,Bedi,G.C.,Engstrom,L.W.,Zeng,Q.,Mookerjee,B.,Gelinas,C.,Fuchs,E.J.,and Bedi,A.Nat.Cell Biol.2001;3,409-416.
9. Brown, S. A., Richards, C. M., Hanscom, H. N., Feng, S. L., and Winkles, J. A. Biochem. J. 2003; 371,395-403.
10. Tran, N. L., McDonough, W. S., Donohue, P. J., Winkles, J. A., Berens, T. J., Ross, K. R., Hoelzinger, D. B., Beaudry, C, Coons, S. W., and Berens, M. E. Am. J. Pathol. 2003; 162, 1313-1321.
11. Shina HM, Kima MH, Kima BH, Jungb SH, Kimc YS, Parka HJ, Honga JT, Mina KR, Kim Y. Inhibitory action of novel aromatic diamine compound on lipopolysaccharide-induced nuclear translocation of NF-kB without affecting IkB degradation. FEBS Letters 2004; 57:150-54.
12. Tran NL, McDonough WS, Donohue PJ, etal. The human Fnl4 receptor gene is up-regulated in migrating glioma cells in vitro and over expressed in advanced glial tumors. Am J Pathol. 2003;162(4): 1313-1321.
1.Fujimori M,Tokino T,Hino O,Kitagawa T,Imamura T,Okamoto E,Mitsunobu M,Ishikawa T,Nakagama H,Harada H.Allelotype study of primary hepatocellular carcinoma.Cancer Res 1991;51:89-93.
2.Okuda K.Hepatocellular carcinoma.J Hepatol 2000;32:225-37.
3.Bosch FX,Ribes J,Diaz M,Cleries R.Primary liver cancer:worldwide incidence and trends.Gastroenterology 2004;127:S5-16.
4.Wands JR.Prevention of hepatocellular carcinoma.New Engl J Med 2004;351:1567-70.
5.Theise ND,Park YN,Kojiro M.Dysplastic nodules and hepatocarcinogenesis.Clin Liver Dis 2002;6:497-512.
6.Weinberg RA.The retinoblastoma protein and cell cycle control.Cell 1995;81:323-330.
7.Wang J,Chenivesse X,Henglein B,et al.Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma.Nature 1990;343:555-557.
8.Ito Y,Matsuura N,Sakon M,et al.Expression and prognostic roles of the G1-S modulators in hepatocellular carcinoma:P27 independently predicts the recurrence.Hepatology 1999;30:90-99.
9.Peng SY,Chou SP,Hsu HC.Association of downregulation of cyclin D1 and of overexpression of cyclin E with p53 mutation,high tumor grade and poor prognosis in hepatocellular carcinoma.J Hepatol 1998;29:281-289.
10.Jung YJ,Lee KH,Choi DW,et al.Reciprocal expressions of cyclin E and cyclin D1inhepatocellular carcinoma.Cancer Lett 2001;168:57-63.
11.Ito Y,Takeda T,Sakon M,et al.Expression of p57/Kip2 protein in hepatocellular carcinoma.Oncology 2001;61:221-225.
12.Fiorentino M,Altimari A,D'Errico A,et al.Acquired expression of p27 is a favorable prognostic indicator in patients with hepatocellular carcinoma.Clin Cancer Res2000;6:3966-3972.
13.Ito Y,Takeda T,Sakon M,et al.Expression and prognostic role of cyclin-dependent kinase 1(cdc2)in hepatocellular carcinoma.Oncology 2000;59:68-74.
14. Tannapfel A, Grund D, Katalinic A, et al. Decreased expression of p27 protein is associated with advanced tumor stage in hepatocellular carcinoma. Int J Cancer 2000; 89:350-355.
15. Nakai S, Masaki T, Shiratori Y, et al. Expression of p57(KIP2) in hepatocellular carcinoma: Relationship between tumor differentiation and patient survival. Int J Oncol 2002; 20:769-775.
16. Feng DY, Zheng H, Tan Y, et al. Effect of phosphorylation of MAPK and Stat3 and expression of c-fos and c-jun proteins on hepatocarcinogenesis and their clinical significance. World J Gastroenterol 2001; 7:33-36,.
17. Schmidt CM, McKillop IH, Cahill PA, et al. Increased MAPK expression and activity in primary human hepatocellular carcinoma. Biochem Biophys Res Commun 1997; 236:54-58.
18. McKillop IH, Schmidt CM, Cahill PA, et al. Altered expression of mitogen-activated protein kinases in a rat model of experimental hepatocellular carcinoma. Hepatology 1997; 26:1484-1491.
19. Ito Y, Sasaki Y, Horimoto M, et al. Activation of mitogen-activated protein kinases/extracellular signal-regulated kinases in human hepatocellular carcinoma. Hepatology 1998; 27:951- 958.
20. Toyoda M, Hashimoto N, Tokita K, et al. Increased activity and expression of MAP kinase in HCC model rats induced by 3_-methyl-4- dimethylamino-azobenzene. J Hepatol 1999; 31:725-733.
21. Giambartolomei S, Covone F, Levrero M, et al. Sustained activation of the Raf/MEK/Erk pathway in response to EGF in stable cell lines expressing the Hepatitis C Virus (HCV) core protein. Oncogene 2001; 20:2606-2610.
22. Tada M, Omata M, Ohto M. Analysis of ras gene mutations in human hepatic malignant tumors by polymerase chain reaction and direct sequencing. Cancer Res 1990; 50:1121-1124.
23. Chao HK, Tsai TF, Lin CS, et al. Evidence that mutational activation of the ras genes may not be involved in aflatoxin B(1)-induced human hepatocarcinog enesis, based on sequence analysis of the ras and p53 genes. Mol Carcinog 1999; 26:69-73.
24. Boivin-Angele S, Lefrancois L, Froment O, et al. Ras gene mutations in vinyl chlorideinduced liver tumours are carcinogen-specific but vary with cell type and species. Int J Cancer 2000; 85:223-227.
25. Xia Q, Yi P, Zhan DJ, et al. Liver tumors induced in B6C3F1 mice by 7-chlorobenz[a] anthracene and 7-bromobenz[a]anthracene contain K-ras protooncogene mutations. Cancer Lett 1998; 123:21-25.
26. Enomoto T, Weghorst CM, Ward JM, et al. Low frequency of H-ras activation in naturally occurring hepatocellular tumors of C3H/HeNCr mice. Carcinogenesis 1993;14:1939-1944.
27. Wogan GN. Aflatoxins as risk factors for hepatocellular carcinoma in humans. Cancer Res 1992; 52:2114s-2118s.
28. Wogan GN. Aflatoxin carcinogenesis: Interspecies potency differences and relevance for human risk assessment. Prog Clin Biol Res 1992; 374: 123-137.
29. Bos JL. The ras gene family and human carcinogenesis. Mutat Res 1988; 195:255-271.
30. Shen HM, Ong CN. Mutations of the p53 tumor suppressor gene and ras oncogenes in aflatoxin hepatocarcinogenesis. Mutat Res 1996; 366: 23-44.
31. Kato K, Cox AD, Hisaka MM, et al. Isoprenoid addition to Ras protein is the critical modification for its membrane association and transforming activity. Proc Natl Acad Sci USA 1992; 89:6403-6407.
32. Guicciardi ME, Gores GJ. Apoptosis: a mechanism of acute and chronic liver injury. Gut 2005; 54: 1024-33.
33. Breitkopf K, Godoy P, Ciuclan L, et al. TGF-beta/Smad signalling in the injured liver. Z Gastroenterol 2006; 44:57-66.
34. Thorgeirsson S S, Teramoto T, Factor V M. Dysregulation of apoptosis in hepatocellular carcinoma. Semin Liver Dis 1998;18:115-22.
35. Fabregat I, Herrera B, Fernandez M, et al. Epidermal growth factor impairs the cytochrome c/caspase-3 apoptotic pathway induced by transforming growth factor beta in rat fetal hepatocytes via a phosphoinositide 3-kinase-dependent pathway. Hepatology 2000; 32: 528-35.
36. Carmona-Cuenca I, Herrera B, Ventura JJ, et al. EGF blocks NADPH oxidase activation by TGF-beta in fetal rat hepatocytes, impairing oxidative stress, and cell death. J Cell Physiol 2006; 207: 322-30.
37. Breuhahn K, Longerich T, Schirmacher P. Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene 2006; 25: 3787-800.
38. Murillo MM, Del Castillo G, Sanchez A, et al. Involvement of EGF receptor and c-Src in the survival signals induced by TGF-beta1 in hepatocytes. Oncogene 2005; 24: 4580-7
39. Arsura M, Cavin LG. Nuclear factor-kB and liver carcinogenesis.Cancer Lett 2005; 229: 157-69.
40. Cavin LG, Wang F, Factor VM, et al. Transforming growth factor-alpha inhibits the intrinsic pathway of c-Myc-induced apoptosis through activation of nuclear factor-kappab in murine hepatocellular carcinomas. Mol Cancer Res 2005; 3: 403-12.
41. Takehara T, Liu X, Fujimoto J, et al. Expression and role of Bcl-xl in human hepatocellular carcinomas. Hepatology 2001; 34: 55-61.
42. Notarbartolo M, Cervello M, Giannitrapani L, et al. Expression of IAPs and alternative splice variants in hepatocellular carcinoma tissues and cells. Ann NY Acad Sci 2004; 1028: 289-93.
43. Kaur S, Wang F, Venkatraman M, Arsura M. X-linked inhibitor of apoptosis (XIAP) inhibits c-Jun N-terminal kinase 1 (JNK1) activation by transforming growth factor beta 1 (TGF-betal) through ubiquitin-mediated proteosomal degradation of the TGF-beta1-activated kinase 1 (TAK1). J Biol Chem 2005; 280: 38599-608.
44. Qiao L, Zhang H, Yu J, et al. Constitutive activation of NF-kappab in human hepatocellular carcinoma: evidence of a cytoprotective role. Human Gene Ther 2006; 17:80-9.
45. Lian Z, Liu J, Pan J, et al. A cellular gene up-regulated by hepatitis B virus-encoded X antigen promotes hepatocellular growth and survival. Hepatology 2001; 34: 146-57.
46. Suzuki A, Hayashida M, Kawano H, et al. Hepatocyte growth factor promotes cell survival from fas-mediated cell death in hepatocellular carcinoma cells via Akt activation and Fasdeath- inducing signaling complex suppression. Hepatology 2000; 32: 796-802.
47. Calvisi DF, Ladu S, Gorden A, et al. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology 2006; 130:1117-28.
48. Kim YC, Song KS, Yoon G, et al. Activated ras oncogene collaborates with hbx gene of hepatitis B virus to transform cells by suppressing HBx-mediated apoptosis. Oncogene 2001; 20: 16-23.
49. Takehara T, Liu X, Fujimoto J, et al. Expression and role of Bcl-xl in human hepatocellular carcinomas. Hepatology 2001; 34: 55-61
50. Sieghart W, Losert D, Strommer S, et al. Mcl-1 overexpression in hepatocellular carcinoma: a potential target for antisense therapy. J Hepatol 2006; 44: 151-7.
51. Beerheide W, Tan YJ, Teng E, et al. Down-regulation of proapoptotic proteins Bax and Bcl-X(S) in p53 overexpression hepatocellular carcinomas. Biochem Biophys Res Commun 2000; 273: 54-61.
52. Gotzmann J, Mikula M, Eger A, et al. Molecular aspects of epithelial cell plasticity: implications for local tumor invasion and metastasis. Mutat Res 2004; 566: 9-20.
53. Valdes F, Alvarez AM, Locascio A, et al. The epithelial mesenchymal transition confers resistance to the apoptotic effects of transforming growth factor beta in fetal rat hepatocytes. Mol Cancer Res 2002; 1: 68-78.
54. Vega S, Morales AV, Ocana OH, et al. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev 2004; 18: 1131-43.
55. Libbrecht L, Desmet V, Roskams T. Preneoplastic lesions in human hepatocarcinogenesis. Liver Int 2006; 25: 16-27.
56. Breuhahn K, Longerich T, Schirmacher P. Dysregulation of growth factor signalling in human hepatocellular carcinoma. Oncogene 2006; 25: 3787-800.
57. Lian Z, Liu J, Li X, et al. Enhanced cell survival of Hep3B cells by the hepatitis Bx antigen effector, URG11, is associated with upregulation of beta-catenin. Hepatology 2006; 43: 415-24.
58. Ribatti D, Vacca A, Dammacco F. The role of the vascular phase in solid tumor growth: a historical review. Neoplasia 1999;1: 293-302.
59. Mignatti P, Rifkin DB. Biology and biochemistry of proteinases in tumor invasion. Physiol Rev 1993;73:161-95.
60. Aznavoorian S, Murphy AN, Stetler-Stevenson WG, Liotta LA. Molecular aspects of tumor cell invasion. Cancer 1993;71: 1368-83.
61. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996;86: 353-64.
62. Peng SH, Deng H, Yang JF, et al. Significance and relationship between infiltrating inflammatory cell and tumor angiogenesis in hepatocellular carcinoma tissues. World J Gastroenterol 2005;11:6521-4.
63. Bingle L, Brown NJ, Lewis CE. The role of tumor associated macrophages in tumor progression: implications for new anticancer therapies. J Pathol 2002;196:254-65.
64. Ribatti D, Crivellato E, Roccaro AM, Ria R, Vacca A. Mast cell contribution to angiogenesis related to tumor progression. Clin Exp Allergy 2004;34:1660-4.
65. Mise M, Arii S, Higashituji H, et al. Clinical significance of vascular endothelial growth factor in normal liver and hepatocellular carcinoma: an immunohistochemical study. Hepatology 1996;23:455-64.
66. Yamaguchi R, Yano H, Iemura A, Ogasawara S, Haramaki M, Kojiro M. Expression of vascular endothelial growth factor in human hepatocellular carcinoma. Hepatology 1998;28:68-77.
67. Park YN, Kim YB, Yang KM, Park C. Increased expression of vascular endothelial growth factor and angiogen
68. Semenza GL. Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. Trends Mol Med 2001;7:345-50.
69. Moon EJ, Jeong CH, Jeong JW, et al. Hepatitis B virus X protein induces angiogenesis by stabilizing hypoxia-inducible factor 1 alpha. FASEB J 2004;18:382-4.
70. El-Assal ON, Yamanoi A, Ono T, Kohno H, Nagasue N. The clinicopathological significance of heparanase and basic fibroblast growth factor expression in hepatocellular carcinoma. Clin Cancer Res 2001;7:1299-305.
71. Poon RT, Hg IO, Lau C, Yu WC, Fan ST, Wong J. Correlation of serum basic fibroblast growth factor levels with clinicopathological features and postoperative recurrence in hepatocellular carcinoma. Am J Surg 2001;182:298-304.
72. Ren B, Yee KO, Lawler J, Khosravi-Far R. Regulation of tumor angiogenesis by thrombospondin-1. Biochim Biophys Acta. 2006 Apr;1765(2):178-88.
73. Steeg PS. Tumor metastasis: mechanistic insights and clinical challenges. Nature Med 2006; 12:895-904.
74. Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nature Rev Cancer 2002;2:563-572
75. Wilson S, Greer B, Hooper J, Zijlstra A, Walker B, Quigley J, et al. The membrane-anchored serine protease, TMPRSS2, activates PAR-2 in prostate cancer cells. Biochem J 2005;388:967-72.
76. Mazzocca A, Coppari R, De Franco R, Cho J, Liebermann TA, Pinzani M, et al. A secreted form of ADAM9 promotes carcinoma invasion through tumor-stromal interactions. Cancer Res 2005;65:4728-38.
77. Hahn WC, Weinberg RA. Rules for making human tumor cells. N Engl J Med 2002;347:1593-1603.
78. Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nature Med 2004;10:789-799.
79. Duffy MJ. The biochemistry of metastasis. Adv Clin Chem 1996;32:135-166.
80. Poste G, Fidler IJ. The pathogenesis of cancer metastasis. Nature 1980;283:139-146.
81. Bernards R, Weinberg RA. A progression puzzle. Nature 2002;418:823.
82. Chambers AF, Tuck AB. Ras-responsive genes and tumor metastasis. Crit Rev Oncog 1993;4:95-114.
83. Yu D, Wang SS, Dulski KM, Tsai CM, Nicolson GL, Hung MC. c-erbB-2/neu overexpression enhances metastatic potential of human lung cancer cells by induction of metastasis-associated properties. Cancer Res 1994;54:3260-3266.
84. Myoui A, Nishimura R, Williams PJ, Hiraga T, Tamura D, Michigami T, et al. C-SRC tyrosine kinase activity is associated with tumor colonization in bone and lung in an animal model of human breast cancer metastasis. Cancer Res 2003;63:5028-5033.
85. Giehl K. Oncogenic Ras in tumour progression and metastasis. Biol. Chem. 2005; 386, 193-205.
86. Liao Y. et al Modulation of apoptosis, tumorigenesity and metastatic potential with antisense H-ras oligodeoxynucleotides in a high metastatic tumor model of hepatoma: LCI-D20. Hepatogastroenterology 2000; 47: 365-370.
87. Varghese HJ et al. Activated ras regulates the proliferation/apoptosis balance and early survival of developing micrometastases. Cancer Res. 2002; 62, 887-891.
88. Roger L, Gadea G, Roux P.Control of cell migration: a tumour suppressor function for p53? Biol Cell. 2006 Mar;98(3): 141-52.
89. Van den Steen PE, Dubois B, Nelissen I, Rudd PM, Dwek RA and Opdenakker G. Biochemistry and molecular biology of gelatinase B or matrix-metalloproteinase-9 (MMP-9). Crit. Rev. Biochem. Mol. Biol. 2002; 37: 375-536.
90. Yoon SO, Park SJ, Yun CH and Chung AS. Roles of matrix metalloproteinases in tumor metastasis and angiogenesis. J. Biochem. Mol. Biol. 2003; 36: 128-137.
91. Hofmann UB, Houben R, Brocker EB and Becker JC. Role of matrix metalloproteinases in melanoma cell invasion. Biochimie 2005; 87: 307-314 .
92. Ozaki I, Yamamoto K, Mizuta T, et al: Differential expression of laminin receptors in human hepatocellular carcinoma. Gut 1998; 43:837- 842.
93. Kleiner DE, Stetler-Stevenson WG: Matrix metalloproteinases and metastasis. Cancer Chemother Pharmacol 1999;43 Suppl:S42-S51.
94. Musso O, Theret N, Campion JP, et al: In situ detection of matrix metalloproteinase-2 (MMP2) and the metalloproteinase inhibitor TIMP2 transcripts in human primary hepatocellular carcinoma and in liver metastasis. J Hepatol 1997;26:593-605.
95. Yamamoto H, Itoh F, Sakamoto H, et al: Association of reduced cell adhesion regulator messenger RNA expression with tumor progression in human hepatocellular carcinoma. Int J Cancer 1997;74:251-254.
96. Harada T, Arii S, Mise M, et al. Membranetype matrix metalloproteinase-1(MT1-MTP) gene is overexpressed in highly invasive hepatocellular carcinomas. J Hepatol 1998;28:231-239.
97. Monvoisin A, Bisson C, Si-Tayeb K, et al. Involvement of matrix metalloproteinase type-3 in hepatocyte growth factor-induced invasion of human hepatocellular carcinoma cells. Int J Cancer 2002;97:157-162.
98. Carloni V, Mazzocca A, Pantaleo P, et al. The integrin, alpha6betal, is necessary for the matrix-dependent activation of FAK and MAP kinase and the migration of human hepatocarcinoma cells. Hepatology 2001;34:42-49.
99. Carloni V, Romanelli RG, Mercurio AM, et al. Knockout of alpha6 beta1-integrin expression reverses the transformed phenotype of hepatocarcinoma cells. Gastroenterology 115:433-442,1998;
100. Torimura T, Ueno T, Kin M, et al. Coordinated expression of integrin alpha6betal and laminin in hepatocellular carcinoma. Hum Pathol 1997;28:1131-1138.
101. Torimura T, Ueno T, Kin M, et al. Integrin alpha6betal plays a significant role in the attachment of hepatoma cells to laminin. J Hepatol 1999;31:734-740.
102. Yao M, Zhou XD, Zha XL, et al. Expression of the integrin alpha5 subunit and its mediated cell adhesion in hepatocellular carcinoma. J Cancer Res Clin Oncol 1997; 123:435-440.
103. Wood Jr S, Holyoke ED, Yardley JH. Mechanisms of metastasis production by blood borne cancer cells. Can Cancer Conf 1966;4:167-223.
104. Fidler IJ. The relationship of embolic homogeneity, number, size and viability to the incidence of experimental metastasis. Eur J Cancer 1973;9:223-7.
105. Ben-Baruch, A.Host microenvironment in breast cancer development: inflammatory cells, cytokines and chemokines in breast cancer progression: reciprocal tumour-microenvironment interactions. Breast Cancer Res 2003; 5: 31-36.
106. Kulbe H, Levinson NR, Balkwill F and Wilson JL. The chemokine network in cancer -much more than directing cell movement. Int. J. Dev. Biol. 2004; 48: 489-496.
107. Sica A, Schioppa T, Mantovani A and Allavena P. Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur. J. Cancer 2006; 42: 717-727.
108. O'Reilly MS et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 1994; 79: 315-328.
109. O'Reilly MS et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 1997;88: 277-285.
2.Okuda K.Hepatocellular carcinoma.J Hepatol 2000;32:225-37.
3.Bosch FX,Ribes J,Diaz M,Clerics R.Primary liver cancer:worldwide incidence and trends.Gastroenterology 2004;127:S5-16.
4.Wands JR.Prevention of hepatocellular carcinoma.New Engl J Med 2004;351:1567-70.
5.Yamamoto J,Kosuge T,Yakayama T,et al.Recurrence of hepatocellular carcinoma after surgery.Br J Surg 1996;83(9):1219-22.
6.Chen XP,Qiu FZ,Wu ZD,et al.Long-term outcome of resection of large hepatocellular carcinoma.Br J Surg 2006;93(5):600-6.
7.Coleman WB.Mechanisms of human hepatocarcinogenesis.Curr Mol Med 2003;3:573-88.
8.Nagasue N,Kohno H,Chang YC,et al.Liver resection for hepatocellular carcinoma.Results of 229 consecutive patients during 11 years.Ann Surg 1993;217:375-384.
9.Bruix J,Boix L,Sala M,Llovet JM.Focus on hepatocellular carcinoma.Cancer Cell 2004;5:215-9.
10.Buendia MA.Genetics of hepatocellular carcinoma.Semin Cancer Biol 2000;10:185-200.
11.Thorgeirsson SS,Grisham JW.Molecular pathogenesis of human hepatocellular carcinoma.Nat Genet 2002;31:339-46.
12.Laurent-Puig P,Zucman-Rossi J.Genetics of hepatocellular tumors.Oncogene 2006;25:3778-86.
13.Farazi PA,Depinho RA.Hepatocellular carcinoma pathogenesis:from genes to environment.Nat Rev Cancer 2006;6:674-87.
14.Feitelson MA,Sun B,Satiroglu Tufan NL,et al.Genetic mechanisms of hepatocarcinogenesis.Oncogene 2002;21:2593-604.
15.Iizuka Net al.Molecular signature in three types of hepatocellular carcinoma with different viral origin by oligonucleotide microarray.Int.J.Oncol 2004;24:565-74.
16.Zhang LH,Ji JF.Molecular profiling of hepatocellular carcinomas by eDNA microarray.World J.Gastroenterol 2005;ll:463-8.Chen X,Cheung ST,So S,et al.Gene expression patterns in human liver cancers.Mol B iol Cell 2002;13:1929-1939.
17.Kim BY,Lee JG,Park S,et al.Feature genes of hepatitis B virus-positive hepatocellular carcinoma,established by its molecular discrimination approach using prediction analysis of microarray.Biochim Biophys Acta 2004;1739:50-61.
18.Neo SY,Leow CK,Vega VB,et al.Identification of discriminators of hepatoma by gene expression profiling using a minimal dataset approach.Hepatology 2004;39:944-953.
19.Xu XR,Huang J,Xu ZG,et al.Insight into hepatocellular carcinogenesis at transcriptome level by comparing gene expression profiles of hepatocellular carcinoma with those of corresponding noncancerous liver. Proc Natl Acad Sci USA 2001;98:15089-15094.
20. Anders RA, Yerian LM, Tretiakova M, et al. cDNA microarray analysis of macroregenerative and dysplastic nodules in end-stage hepatitis C virus-induced cirrhosis. Am J Pathol 2003;162:991-1000.
21. Delpuech O, Trabut JB, Carnot F, et al. Identification, using cDNA macroarray analysis, of distinct gene expression profiles associated with pathological and virological features of hepatocellular carcinoma. Oncogene 2002;21:2926-2937.
22. Iizuka N, Oka M, Yamada-Okabe H, et al. Oligonucleotide microarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection. Lancet 2003;361:923-929.
23. Lee JS, Thorgeirsson SS. Functional and genomic implications of global gene expression profiles in cell lines from human hepatocellular cancer. Hepatology 2002;35:1134- 1143.
24. Okabe H, Satoh S, Kato T, et al. Genome-wide analysis of gene expression in human hepatocellular carcinomas using cDNA microarray: identification of genes involved in viral carcinogenesis and tumor progression. Cancer Res 2001 ;61: 2129-213 7.
25. Paradis V, Bieche I, Dargere D, et al. Molecular profiling of hepatocellular carcinomas (HCC) using a large-scale realtime RT-PCR approach: determination of a molecular diagnostic index. Am J Pathol 2003;163:733-741.
26. Smith MW, Yue ZN, Korth MJ, et al. Hepatitis C virus and liver disease: global transcriptional profiling and identification of potential markers. Hepatology 2003;38:1458-1467.
27. Smith MW, Yue ZN, Geiss GK, et al. Identification of novel tumor markers in hepatitis C virus-associated hepatocellular carcinoma. Cancer Res 2003;63:859-864.
28. Ye QH, Qin LX, Forgues M, et al. Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med 2003 ;9:416-423.
29. Liang P, Averboukh L, Keyomarsi K, Sager R and Pardee AB: Differential display and cloning of messenger RNAs from human breast cancer versus mammary epithelial cells. Cancer Res 1992; 52: 6966-6968.
30. Vasmatzis G, Essand M, Brinkmann U, Lee B and Pastan I: Discovery of three genes specifically expressed in human prostate by expressed sequence tag database analysis. Proc Natl Acad Sci USA 1998; 95: 300-304.
31. Jiang H, Kang DC, Alexandre D and Fisher PB: RaSH, a rapid subtraction hybridization approach for identifying and cloning differentially expressed genes. Proc Natl Acad Sci USA 2000; 97: 12684-12689.
32. Velculescu VE, Zhang L, Vogelstein B and Kinzler KW: Serial analysis of gene expression. Science 270: 484-487, 1995.
33. Schena M, Shalon D, Davis RW and Brown PO: Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science 270: 467-470,1995.
34. Diatchenko L, Lau YF, Campbell AP, Chenchik A, Moqadam F, Huang B, Lukyanov S, Lukyanov K, Gurskaya N, Sverdlov ED and Siebert PD: Suppression subtractive hybridization: a method for generation differentially regulated or tissue-specific cDNA probes and libraries. Proc Natl Acad Sci USA 93: 6025-6030, 1996.
35.Yang GP,Ross DT,Kuang WW,Brown PO and Weigel RJ:Combining SSH and cDNA microarray for rapid identification of differentially expressed genes.Nuceic Acids Res 27:1517-1523,1999.
36.Villaret DB,Wang T,Dillon D,Xu J,Sivam D,Cheever MA and Reed SG:Identification of genes overexpressed in head and neck squamous cell carcinoma using a combination of complementary DNA subtraction and microarray analysis.Laryngoscope 110:374-381,2000.
37.Kojiro M,Roskams T.Early hepatocellular carcinoma and dysplastic nodules.Semin Liver Dis 2005;25:133-142.
38.Grisham JW.Interspecies comparison of liver carcinogenesis:implications for cancer risk assessment.Carcinogenesis 1997;18:59-81.
39.Llovet JM,Burroughs A,Bruix J.Hepatocellular carcinoma.Lancet 2003;362:1907-1917.
40.Van Dyke T,Jacks T.Cancer modeling in the moderu era:progress and challenges.Cell 2002;108:135-144.
41.Klausner RD.Studying cancer in the mouse.Oncogene 1999;18:5249-5252
42.Kojiro M.Histopathology of liver cancers.Best Pract Res Clin Gastroenterol 2005;19:39-62.
43.Yhshijih,Yoshiij,Ikenakay,et al.Inhibition of renninangtotensm system attenuates liber enzyme-altered preneoplastic lesions and fibrosis development in rats.J Hepatal 2002;37(1):22-30.
44.程延安,袁利超,等.间断小剂量DEN诱发大鼠肝癌模型研究.肿瘤防治杂志2005;12(11):806-808.
1.Shuda M,Kondoh N,Tanaka K,Ryo A,Wakatsuki T,Hada A,Goseki N,Igari T,Hatsuse K,Aihara T,Horiuchi S,Shichita M,Yamamoto N and Yamamoto M:Enhanced expression of translation factor mRNAs in hepatocellular carcinoma.Anticancer Res 2000;20:2489-2494.
2.Tarantul VZ,Nikolaev AI,Martynenko A,Hannig H,Hunsmann G and Bodemer W:Differential gene expression in B-cell non-Hodgkin's lymphoma of SIV-infected monkey.AIDS Res Hum Retroviruses2000;16:173-179.
3.Van Duin M,van Marion R,Vissers K,et ah High-resolution array comparative genomic hybridization of chromosome arm 8q:evaluation of genetic progression markers for prostate cancer.Genes Chromosomes Cancer 2005;44:438-449.
4.Leite-Browning ML,McCawley L J,Jahnen-Dechent W,King LE Jr,Matrisian LM and Ochieng J:Alpha 2-HS glycoprotein(fetuin-A)modulates murine skin tumorigenesis.Int J Oncol 2004;25:319-324.
5.Ribom D,westman-Brinkmalm A,Smits A and Davidsson P:Elevated levels of alpha-2-Heremans-Schmid glycoprotein in CSF of patients with low-grade gliomas.Tumour Biol 2003;24:94-99.
6.Morioka Y,Ikeda M,Saiga A,Fujii N,Ishimoto Y,Arita H and Hanasaki K:Potential role of group X secretory phospholipase A(2)in cyclooxygenase-2-dependent PGE(2)formation during colon tumorigenesis.FEBS Lett 2000;487:262-266.
7.Park JW,Park JE,Lee JA,Lee CW and Kim CM:Cyclooxygenase- 2(COX-2)is directly involved but not decisive in proliferation of human hepatocellular carcinoma cells.J Cancer Res Clin Oncol 2006;132:184-192.
8.Zhao QT,Yue SQ,Cui Z,Wang Q,Cui X,Zhai HH,Zhang LH and Dou KF:Potential involvement of the cyclooxygenase-2 pathway in hepatocellular carcinoma-associated angiogenesis.Life Sci 2007;80:484-492.
9.Mosser DD and Morimoto RI:Molecular chaperones and the stress of oncogenesis.Oncogene 2004;23:2907-2918.
10.Jolly C and Morimoto RI:Role of the heat shock response and molecular chaperones in oncogenesis and cell death.J Natl Cancer Inst 2000;92:1564-1572.
11.Malusecka E,Zborek A,Krzyzowska-Gruca S and Krawczyk Z:Expression of heat shock proteins HSP70 and HSP27 in primary non-small cell lung carcinomas.An immunohistochemical study.Anticancer Res 2001;21:1015-1021.
12.Cornford PA,Dodson AR,Parsons KF,Desmond AD,Woolfenden A,Fordham M,Neoptolemos JP,Ke Y and Foster CS:Heat shock protein expression independently predicts clinical outcome in prostate cancer.Cancer Res 2000;60:7099-7105.
13. Rohde M, Daugaard M, Jensen MH, Helin K, Nylandsted J and Jaattela M: Members of the heat-shock protein 70 family promote cancer cell growth by distinct mechanisms. Genes Dev 2005; 19: 570-582.
14. Thornalley PJ: Protecting the genome: defence against nucleotide glycation and emerging role of glyoxalase I overexpression in multidrug resistance in cancer chemotherapy. Biochem Soc Trans 2003; 31: 1372-1377.
15. Filipenko NR, MacLeod TJ, Yoon CS and Waisman DM: Annexin A2 is a novel RNA-binding protein. J Biol Chem 2004; 279: 8723-8731.
16. Gilmore WS, Olwill S, McGlynn H and Alexander HD: Annexin A2 expression during cellular differentiation in myeloid cell lines. Biochem Soc Trans 2004; 32:1122-1123.
17. Tatenhorst L, Rescher U, Gerke V and Paulus W: Knockdown of annexin 2 decreases migration of human glioma cells in vitro. Neuropathol Appl Neurobiol 2006; 32: 271-277.
18. Yoon SY, Kim JM, Oh JH, Jeon YJ, Lee DS, Kim JH, Choi JY, Ahn BM, Kim S, Yoo HS, Kim YS and Kim NS: Gene expression profiling of human HBV- and/or HCV-associated hepatocellular carcinoma cells using expressed sequence tags. Int J Oncol 2006; 29: 315-327.
19. Wang AG, Yoon SY, Oh JH, Jeon YJ, Kim M, Kim JM, Byun SS, Yang JO, Kim JH, Kim DG, Yeom YI, Yoo HS, Kim YS and Kim NS: Identification of intrahepatic cholangiocarcinoma related genes by comparison with normal liver tissues using expressed sequence tags. Biochem Biophys Res Commun 2006; 345:1022-1032.
20. Essner JJ, Chen E and Ekker SC: Syndecan-2. Int J Biochem Cell Biol 2006; 38: 152-156.
21. Kobe B and Deisenhofer J: The leucine-rich repeat: a versatile binding motif. Trends Biochem Sci 1994; 19: 415-421.
22. Kobe B and Deisenhofer J: A structural basis of the interactions between leucine-rich repeats and protein ligands. Nature 1995; 374: 183-186.
23. Bredel M and Pollack IF: The p21-Ras signal transduction pathway and growth regulation in human high-grade gliomas. Brain Res Brain Res Rev 1999; 29: 232-249.
24. Berry-Kravis E and Ciurlionis R: Overexpression of fragile X gene (FMR-1) transcripts increases cAMP production in neural cells. J Neurosci Res 1998; 51: 41-48.
25. Woutersen RA, Appelman LM, van Garderen-Hoetmer A and Feron VJ: Inhalation toxicity of acetaldehyde in rats. III. Carcinogenicity study. Toxicology 1986; 41: 213-231.
26. Caso G, McNurlan MA, McMillan ND, Eremin O and Garlick PJ: Tumour cell growth in culture: dependence on arginine. Clin Sci 2004; 107: 371-379.
27. Yokoyama Y, Kuramitsu Y, Takashima M, Iizuka N, Toda T, Terai S, Sakaida I, Oka M, Nakamura K and Okita K: Proteomic profiling of proteins decreased in hepatocellular carcinoma from patients infected with hepatitis C virus. Proteomics 2004; 4: 2111-2116.
28. Rodriguez-Antona C and Ingelman-Sundberg M: Cytochrome P450 pharmacogenetics and cancer. Oncogene 2006; 25: 1679-1691.
29. Chen J, Xu J, Ying K, Cao G, Hu G, Wang L, Luo C, Lou M, Mao Y, Xie Y and Lu Y: Molecular cloning and characterization of a novel human BTB domain-containing gene, BTBD10, which is down-regulated in glioma. Gene 2004; 340:61-69.
1. Thorgeirsson SS and Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 2002;31, 339 - 346.
2. Lee JS, Chu IS, Heo J, Calvisi DF, Sun Z, Roskams T, Durnez A., Demetris AJ, and Thorgeirsson SS. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology 2004; 40, 667 - 676.
3. Feitelson MA, Pan J, and Lian Z. Early molecular and genetic determinants of primary liver malignancy. Surg Clin North Am 2004; 84,339 - 354.
4. Umeda T, Hino O. Molecular aspects of human hepatocarcinogenesis mediated by inflammation: From hypercarcinogenic state to normo- or hypo carcinogenic state. Oncology 2002; 62 Suppl 138-42.
5. Garber K. Energy boost, the Warburg Effect returns in a new theory of cancer. J Natl Cancer Inst 2004; 96: 1805-6.
6. Young CD, Anderson SM. Sugar and fat - that's where it's at: metabolic changes in tumors.Breast Cancer Res. 2008;10(1):202.
7. Ramanathan A, Wang C, Schreiber SL. Perturbational profiling of a cell-line model of tumorigenesis by using metabolic measurements. Proc Natl Acad Sci USA 2005;102:5992-5997.
8. Pelicano H, Martin DS, Xu RH, Huang P. Glycolysis inhibition for anticancer treatment. Oncogene 2006; 25:4633-4646.
9. Wittig R, Coy JF. The Role of Glucose Metabolism and Glucose-Associated Signalling in Cancer. Perspectives in Medicinal Chemistry 2007; 1:64-82.
10. Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, Zhuang H, Cinalli RM, Alavi A, Rudin CM, Thompson CB. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 2004; 64:3892-3899.
11. Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer 2004; 4:891-899.
12. Stern R, Shuster S, Neudecker BA, Formby B: Lactate stimulates fibroblast expression of hyaluronan and CD44: the Warburg effect revisited. Exp Cell Res 2002; 276:24-31.
13. Walenta S, Wetterling M, Lehrke M, Schwickert G, Sundf0r K, Rofstad EK, Mueller-Klieser W. High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res 2000; 60:916-921.
14. Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, Gottfried E, Schwarz S, Rothe G, Hoves S, Renner K, Timischl B, Mackensen A, Kunz-Schughart L, Andreesen R, Krause SW, Kreutz M. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 2007;109:3812-3819.
15. Philips BJ, Dhir R, Hutzley J, Sen M, Kelavkar UP. Polyunsaturated fatty acid metabolizing 15-Lipoxygenase-1 (15-LO-1) expression in normal and tumorigenic human bladder tissues. Appl Immunohistochem Mol Morphol. 2008;16(2):159-64.
16. Ntambi JM, Miyazaki M, Dobrzyn A.Regulation of stearoyl-CoA desaturase expression. Lipids. 2004;39(11):1061-5.
17. Miyazaki M, Dobrzyn A, Elias PM, Ntambi JM. Stearoyl-CoA desaturase-2 gene expression is required for lipid synthesis during early skin and liver development. Proc Natl Acad Sci USA. 2005;102(35):12501-6.
18. Christianson JL, Nicoloro S, Straubhaar J, Czech MP. Stearoyl-CoA desaturase 2 is required for peroxisome proliferator-activated receptor gamma expression and adipogenesis in cultured 3T3-L1 cells. J Biol Chem. 2008; 283(5):2906-16.
19. Uma RS, Naresh KN, D'Cruz AK, Mulherkar R, Borges AM. Metastasis of squamous cell carcinoma of the oral tongue is associated with down-regulation of epidermal fatty acid binding protein (E-FABP). Oral Oncol. 2007; 43(1):27-32.
20. Ordovas JM. Identification of a functional polymorphism at the adipose fatty acid binding protein gene (FABP4) and demonstration of its association with cardiovascular disease: a path to follow. Nutr Rev. 2007; 65(3): 130-4.
21. Gillilan RE, Ayers SD, Noy N. Structural basis for activation of fatty acid-binding protein 4. J Mol Biol. 2007; 372(5): 1246-60.
22. Rodriguez-Antona C, Ingelman-Sundberg M. Cytochrome P450 pharmacogenetics and cancer. Oncogene. 2006; 25(11): 1679-91.
23. Bergheim I, Wolfgarten E, Bollschweiler E, Holscher AH, Bode C, Parlesak A.Cytochrome P450 levels are altered in patients with esophageal squamous-cell carcinoma. World J Gastroenterol. 2007;13(7):997-1002.
24. McFadyen MC, Murray GI. Cytochrome P450 1B1: a novel anticancer therapeutic target. Future Oncol. 2005;l(2):259-63.
25. Vaclavikova R, Hubackova M, Stribrna-Sarmanova J, Kodet R, Mrhalova M, Novotny J, Gut I, Soucek P.RNA expression of cytochrome P450 in breast cancer patients. Anticancer Res. 2007;27(6C):4443-50.
26. Nebert DW, Dalton TP. The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis. Nat Rev Cancer. 2006;6(12):947-60.
27. Scibior D, Skrzycki M, Podsiad M, Czeczot H. Glutathione level and glutathione-dependent enzyme activities in blood serum of patients with gastrointestinal tract tumors. Clin Biochem. 2008 Mar 20,E pub ahead of print.
28. Pljesa-Ercegovac M, Mimic-Oka J, Dragicevic D, Savic-Radojevic A, Opacic M, Pljesa S, Radosavljevic R, Simic T. Altered antioxidant capacity in human renal cell carcinoma: role of glutathione associated enzymes.Urol Oncol. 2008; 26(2):175-81.
29. Naiki-Ito A, Asamoto M, Hokaiwado N, Takahashi S, Yamashita H, Tsuda H, Ogawa K, Shirai T. Gpx2 is an overexpressed gene in rat breast cancers induced by three different chemical carcinogens. Cancer Res. 2007;67(23): 11353-8.
30. Kipp A, Banning A, Brigelius-Flohe R. Activation of the glutathione peroxidase 2 (GPx2) promoter by beta-catenin. Biol Chem. 2007; 388(10):1027-33.
31. Farber E. Experimental induction of hepatocellular carcinoma as a paradigm for carcinogenesis. Clin Physiol Biochem1987; 5:152 - 159.
32. Hendrich S, Campbell HA, and Pitot HC. Quantitative stereological evaluation of four histochemical markers of altered foci in multistage hepatocarcinogenesis in the rat. Carcinogenesis 1987; 8:1245 - 1250.
33. Higashi K, Hiai H, Higashi T, and Muramatsu M . Regulatory mechanism of glutathione S-transferase P-form during chemical hepatocarcinogenesis: old wine in a new bottle. Cancer Lett 2004; 209:155-163.
34. Hayes JD and Pulford DJ . The glutathione S-transferase supergene family: regulation of GSTand the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol 1995; 30: 445 - 600.
35. Lu SC. Regulation of hepatic glutathione synthesis: current concepts and controversies. FASEB J 1999;13: 1169-1183.
36. Huang ZZ, Chen C, Zeng Z, Yang H, Oh J, Chen L, and Lu SC. Mechanism and significance of increased glutathione level in human hepatocellular carcinoma and liver regeneration. FASEB J 2001; 15: 19 - 21.
37. Schwarz KB, Kew M, Klein A, Abrams RA, Sitzmann J, Jones L, Sharma S, Britton RS, Di Bisceglie AM, and Groopman J. Increased hepatic oxidative DNA damage in patients with hepatocellular carcinoma. Dig Dis Sci 2001; 46:2173 - 2178.
38. Jungst C, Cheng B, Gehrke R, Schmitz V, Nischalke HD, Ramakers J, Schramel P, Schirmacher P, Sauerbruch T, and Caselmann WH. Oxidative damage is increased in human liver tissue adjacent to hepatocellular carcinoma. Hepatology 2004; 39: 1663 -1672.
39. Baumann C, Davies B, Peters M, Kaufmann-Reiche U, Lessl M, Theuring F. AKR1B7 (mouse vas deferens protein) is dispensable for mouse development and reproductive success. Reproduction. 2007;134(1):97-109.
40. Jia G, Takahashi R, Zhang Z, Tsuji Y, Sone H. Aldo-keto reductase 1 family B7 is the gene induced in response to oxidative stress in the livers of Long-Evans Cinnamon rats. Int J Oncol. 2006; 29(4):829-38.
41. Dewa Y, Nishimura J, Muguruma M, Jin M, Saegusa Y, Okamura T, Tasaki M, Umemura T, Mitsumori K.beta-Naphthoflavone enhances oxidative stress responses and the induction of preneoplastic lesions in a diethylnitrosamine-initiated hepatocarcinogenesis model in partially hepatectomized rats. Toxicology. 2008; 244(2-3): 179-89.
42. Ushio-Fukai M, Nakamura Y.Reactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy. Cancer Lett. 2008 Apr 9 [Epub ahead of print]
43. Lee JK, Edderkaoui M, Truong P, Ohno I, Jang KT, Berti A, Pandol SJ, Gukovskaya AS. NADPH oxidase promotes pancreatic cancer cell survival via inhibiting JAK2 dephosphorylation by tyrosine phosphatases. Gastroenterology. 2007; 133(5): 1637-48.
44. Xia C, Meng Q, Liu LZ, Rojanasakul Y, Wang XR, Jiang BH. Reactive oxygen species regulate angiogenesis and tumor growth through vascular endothelial growth factor.Cancer Res. 2007;67(22): 10823-30.
45. Masamune A, Watanabe T, Kikuta K, Satoh K, Shimosegawa T. NADPH oxidase plays a crucial role in the activation of pancreatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2008;294(1):G99-G108.
46. Hendriks WJ, Elson A, Harroch S, Stoker AW. Protein tyrosine phosphatases: functional inferences from mouse models and human diseases. FEBS J. 2008;275(5):816-30.
47. Xing Y, Li Z, Chen Y, Stock JB, Jeffrey PD, Shi Y. Structural mechanism of demethylation and inactivation of protein phosphatase 2A. Cell. 2008;133(1):154-63.
48. Guenin S, Schwartz L, Morvan D, Steyaert JM, Poignet A, Madelmont JC, Demidem A. PP2A activity is controlled by methylation and regulates oncoprotein expression in melanoma cells: a mechanism which participates in growth inhibition induced by chloroethylnitrosourea treatment. Int J Oncol. 2008; 32(1):49-57.
49. Kuo YC, Huang KY, Yang CH, Yang YS, Lee WY, Chiang CW. Regulation of phosphorylation of Thr-308 of Akt, cell proliferation, and survival by the B55alpha regulatory subunit targeting of the protein phosphatase 2A holoenzyme to Akt. J Biol Chem. 2008; 283(4): 1882-92.
50. Junttila MR, Westermarck J. Mechanisms of MYC stabilization in human malignancies. Cell Cycle. 2008; 7(5):592-6.
51. Li X, Chen D, Yin S, Meng Y, Yang H, Landis-Piwowar KR, Li Y, Sarkar FH, Reddy GP, Dou QP, Sheng S. Maspin augments proteasome inhibitor-induced apoptosis in prostate cancer cells J Cell Physiol. 2007; 212(2):298-306.
52. Liu N, Wang Y, Ashton-Rickardt PG. Serine protease inhibitor 2A inhibits caspase-independent cell death. FEBS Lett. 2004; 569(1-3):49-53.
53. Kashima K, Ohike N, Mukai S, Sato M, Takahashi M, Morohoshi T. Expression of the tumor suppressor gene maspin and its significance in intraductal papillary mucinous neoplasms of the pancreas. Hepatobiliary Pancreat Dis Int. 2008; 7(1):86-90.
54. Takahashi H, Sawai H, Funahashi H, Matsuo Y, Yasuda A, Ochi N, Sato M, Okada Y, Takeyama H.Antiproteases in preventing the invasive potential of pancreatic cancer cells. JOP. 2007; 8(4 Suppl):501-8.
55. Hayes MJ, Longbottom RE, Evans MA, Moss SE. Annexinopathies. Subcell Biochem. 2007;45:l-28.
56. Brichory FM, Misek DE, Yim AM, et al. An immune response manifested by the common occurrence of Annexin I and Annexin II autoantibodies and high circulating levels of IL-6 in lung cancer. Proc Natl Acad Sci USA 2001; 98:9824-9829.
57. Emoto K, Yamada Y, Sawada H, et al. Annexin II overexpression correlates with stromal tenascin-C overexpression: a prognostic marker in colorectal carcinoma. Cancer 2001; 92:1419-1426.
58. Morel E, Gruenberg J. The p11/S100A10 light chain of annexin A2 is dispensable for annexin A2 association to endosomes and functions in endosomal transport. PLoS ONE. 2007 Oct 31;2(10):e1118.
59. Ito Y, Arai K, Nozawa R, Yoshida H, Higashiyama T, Takamura Y, Miya A, Kobayashi K, Kuma K, Miyauchi A. S100A10 expression in thyroid neoplasms originating from the follicular epithelium: contribution to the aggressive characteristic of anaplastic carcinoma. Anticancer Res. 2007; 27(4C):2679-83.
60. Zhang Y, Zhou ZH, Bugge TH, Wahl LM. Urokinase-type plasminogen activator stimulation of monocyte matrix metalloproteinase-1 production is mediated by plasmin-dependent signaling through annexin A2 and inhibited by inactive plasmin. J Immunol. 2007;179(5):3297-304.
61. Full en DR, Garrisi AJ, Sanders D, Thomas D. Expression of S100A6 protein in a broad spectrum of cutaneous tumors using tissue microarrays. J Cutan Pathol. 2008 Jan 14 [Epub ahead of print]
62. Ghavami S, Rashedi I, Dattilo BM, Eshraghi M, Chazin WJ, Hashemi M, Wesselborg S, Kerkhoff C, Los M. S100A8/A9 at low concentration promotes tumor cell growth via RAGE ligation and MAP kinase-dependent pathway. J Leukoc Biol. 2008 Mar 13 [Epub ahead of print]
63. Kim HJ, Kim JB, Lee KM, Shin I, Han W, Ko E, Bae JY, Noh DY. Isolation of CD24(high) and CD24(low/-) cells from MCF-7: CD24 expression is positively related with proliferation, adhesion and invasion in MCF-7. Cancer Lett. 2007; 258(1):98-108.
64. Sagiv E, Memeo L, Karin A, Kazanov D, Jacob-Hirsch J, Mansukhani M, Rechavi G, Hibshoosh H, Arber N. CD24 is a new oncogene, early at the multistep process of colorectal cancer carcinogenesis. Gastroenterology. 2006;131(2):630-9.
65. Chou YY, Jeng YM, Lee TT, Hu FC, Kao HL, Lin WC, Lai PL, Hu RH, Yuan RH. Cytoplasmic CD24 expression is a novel prognostic factor in diffuse-type gastric adenocarcinoma. Ann Surg Oncol. 2007;14(10):2748-58.
66. Kwon GY, Ha H, Ahn G, Park SY, Huh SJ, Park W. Role of CD24 protein in predicting metastatic potential of uterine cervical squamous cell carcinoma in patients treated with radiotherapy. Int J Radiat Oncol Biol Phys. 2007; 69(4): 1150-6.
67. Agrawal S, Kuvshinoff BW, Khoury T, Yu J, Javle MM, LeVea C, Groth J, Coignet LJ, Gibbs JF. CD24 expression is an independent prognostic marker in cholangiocarcinoma. J Gastrointest Surg. 2007; 11(4):445-51.
68. Looi LM, Cheah PL, Zhao W, Ng MH, Yip CH. CD44 expression and axillary lymph node metastasis in infiltrating ductal carcinoma of the breast. Malays J Pathol. 2006; 28(2):83-6.
69. Lee SM, Lee KE, Chang HJ, Choi MY, Cho MS, Min SK, Lee HK, Mun YC, Nam EM, Seong CM, Lee SN.Ann Surg Oncol. Prognostic significance of CD44s expression in biliary tract cancers. 2008; 15(4): 1155-60.
70. Lim SD, Young AN, Paner GP, Amin MB. Prognostic role of CD44 cell adhesion molecule expression in primary and metastatic renal cell carcinoma: a clinicopathologic study of 125 cases. Virchows Arch. 2008; 452(1):49-55.
71. Ouhtit A, Abd Elmageed ZY, Abdraboh ME, Lioe TF, Raj MH. In vivo evidence for the role of CD44s in promoting breast cancer metastasis to the liver. Am J Pathol. 2007;171(6):2033-9.
72. Stein R, Mattes MJ, Cardillo TM, Hansen HJ, Chang CH, Burton J, Govindan S, Goldenberg DM.Clin Cancer Res. CD74: a new candidate target for the immunotherapy of B-cell neoplasms. 2007;13(18 Pt 2):5556s-5563s.
73. Shi X, Leng L, Wang T, Wang W, Du X, Li J, McDonald C, Chen Z, Murphy JW, Lolis E, Noble P, Knudson W, Bucala R. CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex. Immunity. 2006; 25(4):595-606.
74. Beswick EJ, Pinchuk IV, Suarez G, Sierra JC, Reyes VE. Helicobacter pylori CagA-dependent macrophage migration inhibitory factor produced by gastric epithelial cells binds to CD74 and stimulates procarcinogenic events. J Immunol. 2006;176(11):6794-801.
75. Koide N, Yamada T, Shibata R, Mori T, Fukuma M, Yamazaki K, Aiura K, Shimazu M, Hirohashi S, Nimura Y, Sakamoto M. Establishment of perineural invasion models and analysis of gene expression revealed an invariant chain (CD74) as a possible molecule involved in perineural invasion in pancreatic cancer. Clin Cancer Res. 2006;12(8):2419-26.
76. Hahn WC, Weinberg RA. Rules for making human tumor cells. N Engl J Med 2002;347:1593-1603.; Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nature Med 2004; 10:789-799.
77. Duffy MJ. The biochemistry of metastasis. Adv Clin Chem 1996;32:135-166.
78. Poste G, Fidler IJ. The pathogenesis of cancer metastasis. Nature 1980;283:139-146.
79. Bernards R, Weinberg RA. A progression puzzle. Nature 2002;418:823.
80. Duffy MJ, Kelly ZD, Culhane AC, O'Brien A, Gallagher WM. DNA microarray-based gene expression profiling in cancer: aiding cancer diagnosis, assessing prognosis and predicting response to therapy. Curr Pharmacogenomics 2005 ;3: 289-304.
81. Chambers AF, Tuck AB. Ras-responsive genes and tumor metastasis. Crit Rev Oncog 1993;4:95-114.
82. Yu D, Wang SS, Dulski KM, Tsai CM, Nicolson GL, Hung MC. c-erbB-2/neu overexpression enhances metastatic potential of human lung cancer cells by induction of metastasis-associated properties. Cancer Res 1994;54:3260—3266.
83. Myoui A, Nishimura R, Williams PJ, Hiraga T, Tamura D, Michigami T, et al. C-SRC tyrosine kinase activity is associated with tumor colonization in bone and lung in an animal model of human breast cancer metastasis. Cancer Res 2003;63:5028-5033.
84. Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nature Rev Cancer 2002;2:161-174.
85. Duffy MJ. The urokinase plasminogen activator system: role in malignancy. Curr Pharm Des2004;10:39-49.
86. Parekh S, Prive G, Melnick A. Therapeutic targeting of the Bcl6 oncogene for diffuse large B-cell lymphomas. Leuk Lymphoma. 2008; 49(5):874-82.
87. Perez-Rosado A, Artiga M, Vargiu P, Sanchez-Aguilera A, Alvarez-Barrientos A, Piris M. BCL6 represses NFkappaB activity in diffuse large B-cell lymphomas. J Pathol. 2008;214(4):498-507.
88. Zhang J, Chen S, Zhang W, Zhang J, Liu X, Shi H, Che H, Wang W, Li F, Yao L. Human differentiation-related gene NDRG1 is a Myc downstream-regulated gene that is repressed by Myc on the core promoter region. Gene. 2008 Mar 12 [Epub ahead of print]
89. Kovacevic Z, Richardson DR. The metastasis suppressor, Ndrg-1: a new ally in the fight against cancer. Carcinogenesis. 2006; 27(12):2355-66.
90. Zhang J, Li F, Liu X, Shen L, Liu J, Su J, Zhang W, Deng Y, Wang L, Liu N, Han W, Zhang J, Ji S, Yang A, Han H, Yao L.The repression of human differentiation-related gene NDRG2 expression by Myc via Miz-1-dependent interaction with the NDRG2 core promoter. J Biol Chem. 2006; 281(51):39159-68.
91. Wang L, Liu N, Yao L, Li F, Zhang J, Deng Y, Liu J, Ji S, Yang A, Han H, Zhang Y, Zhang J, Han W, Liu X. NDRG2 is a new HIF-1 target gene necessary for hypoxia-induced apoptosis in A549 cells. Cell Physiol Biochem. 2008;21(1-3):239-50.
92. Choi SC, Yoon SR, Park YP, Song EY, Kim JW, Kim WH, Yang Y, Lim JS, Lee HG.Expression of NDRG2 is related to tumor progression and survival of gastric cancer patients through Fas-mediated cell death. Exp Mol Med. 2007; 39(6):705-14.
93. Lorentzen A, Vogel LK, Lewinsky RH, Saeb0 M, Skjelbred CF, Godiksen S, Hoff G, Tveit KM, Lothe IM, Ikdahl T, Kure EH, Mitchelmore C. Expression of NDRG2 is down-regulated in high-risk adenomas and colorectal carcinoma. BMC Cancer. 2007; 7:192.
94. Park Y, Shon SK, Kim A, Kim KI, Yang Y, Cho DH, Lee MS, Lim JS.SOCS1 induced by NDRG2 expression negatively regulates STAT3 activation in breast cancer cells. Biochem Biophys Res Commun. 2007; 363(2):361-7.
95. Hsieh YS, Lee YL, Yang SF, Yang JS, Chen W, Chen SC, Shih CM. Association of EcoRI polymorphism of the metastasis-suppressor gene NME1 with susceptibility to and severity of non-small cell lung cancer. Lung Cancer. 2007; 58(2):191-5.
96. Sers C, Husmann K, Nazarenko I, Reich S, Wiechen K, Zhumabayeva B, Adhikari P, Schroder K, Gontarewicz A, Schafer R.The class II tumour suppressor gene H-REV107-1 is a target of interferon-regulatory factor-1 and is involved in IFNgamma-induced cell death in human ovarian carcinoma cells. Oncogene. 2002 Apr 25;21(18):2829-39.
97. Siegrist S, Feral C, Chami M, Solhonne B, Mattei MG, Rajpert-De Meyts E, Guellaen G, Bulle F. hH-RevlO7, a class II tumor suppressor gene, is expressed by post-meiotic testicular germ cells and CIS cells but not by human testicular germ cell tumors. Oncogene. 2001;20(37):5155-63.
98. Nazarenko I, Schafer R, Sers C. Mechanisms of the HRSL3 tumor suppressor function in ovarian carcinoma cells. J Cell Sci. 2007;120(Pt 8):1393-404.
99. R.A. Cairns, R. Khokha, R.P. Hill, Molecular mechanisms of tumor invasion and metastasis: an integrated view. Curr Mol Med2003; 3: 659-671.
100. L.M. Coussens, Z.Werb, Inflammation and cancer. Nature 2002; 420: 860-867.
101.Grigioni WF, Garbisa S, D'Errico A, et al. Evaluation of hepatocellular carcinoma aggressiveness by a panel of extracellular matrix antigens. Am J Pathol 1991 ;138: 647-54.
102. Torimura T, Ueno T, Inuzuka S, et al. The extracellular matrix in hepatocellular carcinoma shows different localization patterns depending on the differentiation and the histological pattern of tumors: immunohistochemical analysis. J Hepatol 1994; 21:37-46.].
103. Bissell DM. Chronic liver injury, TGF-beta, and cancer. Exp Mol Med 2001;33:179-90.
104. Yoshiji H, Kuriyama S, Yoshii J, et al. Extracellular matrix remodeling may predominate over hepatocyte injury in hepatocellular carcinoma development. Oncol Rep 2003;10:957-62.
105. Carloni V, Romanelli RG, Mercurio AM, et al. Knockout of alpha6beta1-integrin expression reverses the transformed phenotype of hepatocarcinoma cells. Gastroenterology 1998;115:433-42.
106. Yang C, Zeisberg M, Lively JC, Nyberg P, Afdhal N, Kalluri R. Integrin alphalbetal and alpha2betal are the key regulators of hepatocarcinoma cell invasion across the fibrotic matrix microenvironment. Cancer Res 2003;63:8312—7.
107. Giannelli G, Bergamini C, Fransvea E, Marinosci F, Quaranta V, Antonaci S. Human hepatocellular carcinoma (HCC) cells require both alpha3beta1 integrin and matrix metalloproteinases activity for migration and invasion. Lab Invest 2001;81:613-27.
108. Fu BH, Wu ZZ, Dong C. Integrin beta1 mediates hepatocellular carcinoma cells chemotaxis to laminin. Hepatobiliary Pancreat Dis Int 2004;3:548-51.
109. Le Bail B, Faouzi S, Boussarie L, Balabaud C, Bioulac-Sage P, Rosenbaum J. Extracellular matrix composition and integrin expression in early hepatocarcinogenesis in human cirrhotic liver. J Pathol 1997;181:330-7.
110. Cariati M, Naderi A, Brown JP, Smalley MJ, Pinder SE, Caldas C, Purushotham AD.Alpha-6 integrin is necessary for the tumourigenicity of a stem cell-like subpopulation within the MCF7 breast cancer cell line. Int J Cancer. 2008;122(2):298-304.
111. Zhang H, Ozaki I, Mizuta T, et al. Transforming growth factor-beta1-induced apoptosis is blocked by beta1-integrin- mediated mitogen-activated protein kinase activation in human hepatoma cells. Cancer Sci 2004;95: 878-86.
112. Zhang H, Ozaki I, Mizuta T, et al. Beta1-integrin protects hepatoma cells from chemotherapy induced apoptosis via a mitogen-activated protein kinase dependent pathway. Cancer 2002;95:896-906.
113. Tian B, Li Y, Ji XN, et al. Basement membrane proteins play an active role in the invasive process of human hepatocellular carcinoma cells with high metastasis potential. J Cancer Res Clin Oncol 2005; 131:80-6.
114. Torbenson M, Wang J, Choti M, et al. Hepatocellular carcinomas show abnormal expression of fibronectin protein. Mod Pathol 2002; 15:826-30.
115. Coussens, L. M. and Werb, Z. Inflammation and cancer. Nature 2002; 420: 860-867.
116. Slaga TJ, Lichti U, Hennings H, Elgjo K, Yuspa SH. Effects of tumor promoters and steroidal anti-inflammatory agents on skin of newborn mice in vivo and in vitro. J Natl Cancer Inst 1978;60:425-31.
117. Jackson JR, Seed MP, Kircher CH, Willoughby DA, Winkler JD. The codependence of angiogenesis and chronic inflammation. FASEB J 1997;11:457—65.
118. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100:57-70.
1.Feng SL,Guo Y,Factor VM,etal.The Fnl4 immediate early response gene is induced during liver regeneration and highly expressed in both human and murine hepatocellular carcinomas.Am J Pathol,2000;156(4):1253-1261.
2.Tran NL,McDonough WS,Savitch BA,Fortin SP,Winkles JA,Symons M,Nakada M,Cunliffe HE,Hostetter G,Hoelzinger DB,Rennert JL,Michaelson JS,Burkly LC,Lipinski CA,Loflus JC,Mariani L,Berens ME.Increased Fibroblast Growth Factor-Inducible 14Expression Levels Promote Glioma Cell Invasion via Racl and Nuclear Factor-{kappa}B and Correlate with Poor Patient Outcome.Cancer Res.2006;66(19):9535-42.
3.Tran NL,McDonough WS,Savitch BA,Sawyer TF,Winkles JA,Berens ME.The tumor necrosis factor-like weak inducer of apoptosis(TWEAK)-fibroblast growth factor-inducible 14(Fnl4)signaling system regulates glioma cell survival via NFkappaB pathway activation and BCL-XL/BCL-W expression.J Biol Chem.2005;280(5):3483-92.
4.Lee JS,Thorgeirsson SS.Comparative and integrative functional genomics of HCC.Oncogene 2006;25:3801-9.
5.Yamagishi,N.,Miyakoshi,J.,and Takebe,H.Int.J.Radiat.Biol.1997;72,157-162.
6.Miyakoshi,J.,and Yagi,K.Br.J.Cancer 2000;82,28-33.
7.Ding,G.R.,Honda,N.,Nakahara,T.,Tian,F.,Yoshida,M.,Hirose,H.,and Miyakoshi,J.Radiat.Res.2003;160,232-237.
8.Ravi,R.,Bedi,G.C.,Engstrom,L.W.,Zeng,Q.,Mookerjee,B.,Gelinas,C.,Fuchs,E.J.,and Bedi,A.Nat.Cell Biol.2001;3,409-416.
9. Brown, S. A., Richards, C. M., Hanscom, H. N., Feng, S. L., and Winkles, J. A. Biochem. J. 2003; 371,395-403.
10. Tran, N. L., McDonough, W. S., Donohue, P. J., Winkles, J. A., Berens, T. J., Ross, K. R., Hoelzinger, D. B., Beaudry, C, Coons, S. W., and Berens, M. E. Am. J. Pathol. 2003; 162, 1313-1321.
11. Shina HM, Kima MH, Kima BH, Jungb SH, Kimc YS, Parka HJ, Honga JT, Mina KR, Kim Y. Inhibitory action of novel aromatic diamine compound on lipopolysaccharide-induced nuclear translocation of NF-kB without affecting IkB degradation. FEBS Letters 2004; 57:150-54.
12. Tran NL, McDonough WS, Donohue PJ, etal. The human Fnl4 receptor gene is up-regulated in migrating glioma cells in vitro and over expressed in advanced glial tumors. Am J Pathol. 2003;162(4): 1313-1321.
1.Fujimori M,Tokino T,Hino O,Kitagawa T,Imamura T,Okamoto E,Mitsunobu M,Ishikawa T,Nakagama H,Harada H.Allelotype study of primary hepatocellular carcinoma.Cancer Res 1991;51:89-93.
2.Okuda K.Hepatocellular carcinoma.J Hepatol 2000;32:225-37.
3.Bosch FX,Ribes J,Diaz M,Cleries R.Primary liver cancer:worldwide incidence and trends.Gastroenterology 2004;127:S5-16.
4.Wands JR.Prevention of hepatocellular carcinoma.New Engl J Med 2004;351:1567-70.
5.Theise ND,Park YN,Kojiro M.Dysplastic nodules and hepatocarcinogenesis.Clin Liver Dis 2002;6:497-512.
6.Weinberg RA.The retinoblastoma protein and cell cycle control.Cell 1995;81:323-330.
7.Wang J,Chenivesse X,Henglein B,et al.Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma.Nature 1990;343:555-557.
8.Ito Y,Matsuura N,Sakon M,et al.Expression and prognostic roles of the G1-S modulators in hepatocellular carcinoma:P27 independently predicts the recurrence.Hepatology 1999;30:90-99.
9.Peng SY,Chou SP,Hsu HC.Association of downregulation of cyclin D1 and of overexpression of cyclin E with p53 mutation,high tumor grade and poor prognosis in hepatocellular carcinoma.J Hepatol 1998;29:281-289.
10.Jung YJ,Lee KH,Choi DW,et al.Reciprocal expressions of cyclin E and cyclin D1inhepatocellular carcinoma.Cancer Lett 2001;168:57-63.
11.Ito Y,Takeda T,Sakon M,et al.Expression of p57/Kip2 protein in hepatocellular carcinoma.Oncology 2001;61:221-225.
12.Fiorentino M,Altimari A,D'Errico A,et al.Acquired expression of p27 is a favorable prognostic indicator in patients with hepatocellular carcinoma.Clin Cancer Res2000;6:3966-3972.
13.Ito Y,Takeda T,Sakon M,et al.Expression and prognostic role of cyclin-dependent kinase 1(cdc2)in hepatocellular carcinoma.Oncology 2000;59:68-74.
14. Tannapfel A, Grund D, Katalinic A, et al. Decreased expression of p27 protein is associated with advanced tumor stage in hepatocellular carcinoma. Int J Cancer 2000; 89:350-355.
15. Nakai S, Masaki T, Shiratori Y, et al. Expression of p57(KIP2) in hepatocellular carcinoma: Relationship between tumor differentiation and patient survival. Int J Oncol 2002; 20:769-775.
16. Feng DY, Zheng H, Tan Y, et al. Effect of phosphorylation of MAPK and Stat3 and expression of c-fos and c-jun proteins on hepatocarcinogenesis and their clinical significance. World J Gastroenterol 2001; 7:33-36,.
17. Schmidt CM, McKillop IH, Cahill PA, et al. Increased MAPK expression and activity in primary human hepatocellular carcinoma. Biochem Biophys Res Commun 1997; 236:54-58.
18. McKillop IH, Schmidt CM, Cahill PA, et al. Altered expression of mitogen-activated protein kinases in a rat model of experimental hepatocellular carcinoma. Hepatology 1997; 26:1484-1491.
19. Ito Y, Sasaki Y, Horimoto M, et al. Activation of mitogen-activated protein kinases/extracellular signal-regulated kinases in human hepatocellular carcinoma. Hepatology 1998; 27:951- 958.
20. Toyoda M, Hashimoto N, Tokita K, et al. Increased activity and expression of MAP kinase in HCC model rats induced by 3_-methyl-4- dimethylamino-azobenzene. J Hepatol 1999; 31:725-733.
21. Giambartolomei S, Covone F, Levrero M, et al. Sustained activation of the Raf/MEK/Erk pathway in response to EGF in stable cell lines expressing the Hepatitis C Virus (HCV) core protein. Oncogene 2001; 20:2606-2610.
22. Tada M, Omata M, Ohto M. Analysis of ras gene mutations in human hepatic malignant tumors by polymerase chain reaction and direct sequencing. Cancer Res 1990; 50:1121-1124.
23. Chao HK, Tsai TF, Lin CS, et al. Evidence that mutational activation of the ras genes may not be involved in aflatoxin B(1)-induced human hepatocarcinog enesis, based on sequence analysis of the ras and p53 genes. Mol Carcinog 1999; 26:69-73.
24. Boivin-Angele S, Lefrancois L, Froment O, et al. Ras gene mutations in vinyl chlorideinduced liver tumours are carcinogen-specific but vary with cell type and species. Int J Cancer 2000; 85:223-227.
25. Xia Q, Yi P, Zhan DJ, et al. Liver tumors induced in B6C3F1 mice by 7-chlorobenz[a] anthracene and 7-bromobenz[a]anthracene contain K-ras protooncogene mutations. Cancer Lett 1998; 123:21-25.
26. Enomoto T, Weghorst CM, Ward JM, et al. Low frequency of H-ras activation in naturally occurring hepatocellular tumors of C3H/HeNCr mice. Carcinogenesis 1993;14:1939-1944.
27. Wogan GN. Aflatoxins as risk factors for hepatocellular carcinoma in humans. Cancer Res 1992; 52:2114s-2118s.
28. Wogan GN. Aflatoxin carcinogenesis: Interspecies potency differences and relevance for human risk assessment. Prog Clin Biol Res 1992; 374: 123-137.
29. Bos JL. The ras gene family and human carcinogenesis. Mutat Res 1988; 195:255-271.
30. Shen HM, Ong CN. Mutations of the p53 tumor suppressor gene and ras oncogenes in aflatoxin hepatocarcinogenesis. Mutat Res 1996; 366: 23-44.
31. Kato K, Cox AD, Hisaka MM, et al. Isoprenoid addition to Ras protein is the critical modification for its membrane association and transforming activity. Proc Natl Acad Sci USA 1992; 89:6403-6407.
32. Guicciardi ME, Gores GJ. Apoptosis: a mechanism of acute and chronic liver injury. Gut 2005; 54: 1024-33.
33. Breitkopf K, Godoy P, Ciuclan L, et al. TGF-beta/Smad signalling in the injured liver. Z Gastroenterol 2006; 44:57-66.
34. Thorgeirsson S S, Teramoto T, Factor V M. Dysregulation of apoptosis in hepatocellular carcinoma. Semin Liver Dis 1998;18:115-22.
35. Fabregat I, Herrera B, Fernandez M, et al. Epidermal growth factor impairs the cytochrome c/caspase-3 apoptotic pathway induced by transforming growth factor beta in rat fetal hepatocytes via a phosphoinositide 3-kinase-dependent pathway. Hepatology 2000; 32: 528-35.
36. Carmona-Cuenca I, Herrera B, Ventura JJ, et al. EGF blocks NADPH oxidase activation by TGF-beta in fetal rat hepatocytes, impairing oxidative stress, and cell death. J Cell Physiol 2006; 207: 322-30.
37. Breuhahn K, Longerich T, Schirmacher P. Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene 2006; 25: 3787-800.
38. Murillo MM, Del Castillo G, Sanchez A, et al. Involvement of EGF receptor and c-Src in the survival signals induced by TGF-beta1 in hepatocytes. Oncogene 2005; 24: 4580-7
39. Arsura M, Cavin LG. Nuclear factor-kB and liver carcinogenesis.Cancer Lett 2005; 229: 157-69.
40. Cavin LG, Wang F, Factor VM, et al. Transforming growth factor-alpha inhibits the intrinsic pathway of c-Myc-induced apoptosis through activation of nuclear factor-kappab in murine hepatocellular carcinomas. Mol Cancer Res 2005; 3: 403-12.
41. Takehara T, Liu X, Fujimoto J, et al. Expression and role of Bcl-xl in human hepatocellular carcinomas. Hepatology 2001; 34: 55-61.
42. Notarbartolo M, Cervello M, Giannitrapani L, et al. Expression of IAPs and alternative splice variants in hepatocellular carcinoma tissues and cells. Ann NY Acad Sci 2004; 1028: 289-93.
43. Kaur S, Wang F, Venkatraman M, Arsura M. X-linked inhibitor of apoptosis (XIAP) inhibits c-Jun N-terminal kinase 1 (JNK1) activation by transforming growth factor beta 1 (TGF-betal) through ubiquitin-mediated proteosomal degradation of the TGF-beta1-activated kinase 1 (TAK1). J Biol Chem 2005; 280: 38599-608.
44. Qiao L, Zhang H, Yu J, et al. Constitutive activation of NF-kappab in human hepatocellular carcinoma: evidence of a cytoprotective role. Human Gene Ther 2006; 17:80-9.
45. Lian Z, Liu J, Pan J, et al. A cellular gene up-regulated by hepatitis B virus-encoded X antigen promotes hepatocellular growth and survival. Hepatology 2001; 34: 146-57.
46. Suzuki A, Hayashida M, Kawano H, et al. Hepatocyte growth factor promotes cell survival from fas-mediated cell death in hepatocellular carcinoma cells via Akt activation and Fasdeath- inducing signaling complex suppression. Hepatology 2000; 32: 796-802.
47. Calvisi DF, Ladu S, Gorden A, et al. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology 2006; 130:1117-28.
48. Kim YC, Song KS, Yoon G, et al. Activated ras oncogene collaborates with hbx gene of hepatitis B virus to transform cells by suppressing HBx-mediated apoptosis. Oncogene 2001; 20: 16-23.
49. Takehara T, Liu X, Fujimoto J, et al. Expression and role of Bcl-xl in human hepatocellular carcinomas. Hepatology 2001; 34: 55-61
50. Sieghart W, Losert D, Strommer S, et al. Mcl-1 overexpression in hepatocellular carcinoma: a potential target for antisense therapy. J Hepatol 2006; 44: 151-7.
51. Beerheide W, Tan YJ, Teng E, et al. Down-regulation of proapoptotic proteins Bax and Bcl-X(S) in p53 overexpression hepatocellular carcinomas. Biochem Biophys Res Commun 2000; 273: 54-61.
52. Gotzmann J, Mikula M, Eger A, et al. Molecular aspects of epithelial cell plasticity: implications for local tumor invasion and metastasis. Mutat Res 2004; 566: 9-20.
53. Valdes F, Alvarez AM, Locascio A, et al. The epithelial mesenchymal transition confers resistance to the apoptotic effects of transforming growth factor beta in fetal rat hepatocytes. Mol Cancer Res 2002; 1: 68-78.
54. Vega S, Morales AV, Ocana OH, et al. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev 2004; 18: 1131-43.
55. Libbrecht L, Desmet V, Roskams T. Preneoplastic lesions in human hepatocarcinogenesis. Liver Int 2006; 25: 16-27.
56. Breuhahn K, Longerich T, Schirmacher P. Dysregulation of growth factor signalling in human hepatocellular carcinoma. Oncogene 2006; 25: 3787-800.
57. Lian Z, Liu J, Li X, et al. Enhanced cell survival of Hep3B cells by the hepatitis Bx antigen effector, URG11, is associated with upregulation of beta-catenin. Hepatology 2006; 43: 415-24.
58. Ribatti D, Vacca A, Dammacco F. The role of the vascular phase in solid tumor growth: a historical review. Neoplasia 1999;1: 293-302.
59. Mignatti P, Rifkin DB. Biology and biochemistry of proteinases in tumor invasion. Physiol Rev 1993;73:161-95.
60. Aznavoorian S, Murphy AN, Stetler-Stevenson WG, Liotta LA. Molecular aspects of tumor cell invasion. Cancer 1993;71: 1368-83.
61. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996;86: 353-64.
62. Peng SH, Deng H, Yang JF, et al. Significance and relationship between infiltrating inflammatory cell and tumor angiogenesis in hepatocellular carcinoma tissues. World J Gastroenterol 2005;11:6521-4.
63. Bingle L, Brown NJ, Lewis CE. The role of tumor associated macrophages in tumor progression: implications for new anticancer therapies. J Pathol 2002;196:254-65.
64. Ribatti D, Crivellato E, Roccaro AM, Ria R, Vacca A. Mast cell contribution to angiogenesis related to tumor progression. Clin Exp Allergy 2004;34:1660-4.
65. Mise M, Arii S, Higashituji H, et al. Clinical significance of vascular endothelial growth factor in normal liver and hepatocellular carcinoma: an immunohistochemical study. Hepatology 1996;23:455-64.
66. Yamaguchi R, Yano H, Iemura A, Ogasawara S, Haramaki M, Kojiro M. Expression of vascular endothelial growth factor in human hepatocellular carcinoma. Hepatology 1998;28:68-77.
67. Park YN, Kim YB, Yang KM, Park C. Increased expression of vascular endothelial growth factor and angiogen
68. Semenza GL. Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. Trends Mol Med 2001;7:345-50.
69. Moon EJ, Jeong CH, Jeong JW, et al. Hepatitis B virus X protein induces angiogenesis by stabilizing hypoxia-inducible factor 1 alpha. FASEB J 2004;18:382-4.
70. El-Assal ON, Yamanoi A, Ono T, Kohno H, Nagasue N. The clinicopathological significance of heparanase and basic fibroblast growth factor expression in hepatocellular carcinoma. Clin Cancer Res 2001;7:1299-305.
71. Poon RT, Hg IO, Lau C, Yu WC, Fan ST, Wong J. Correlation of serum basic fibroblast growth factor levels with clinicopathological features and postoperative recurrence in hepatocellular carcinoma. Am J Surg 2001;182:298-304.
72. Ren B, Yee KO, Lawler J, Khosravi-Far R. Regulation of tumor angiogenesis by thrombospondin-1. Biochim Biophys Acta. 2006 Apr;1765(2):178-88.
73. Steeg PS. Tumor metastasis: mechanistic insights and clinical challenges. Nature Med 2006; 12:895-904.
74. Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nature Rev Cancer 2002;2:563-572
75. Wilson S, Greer B, Hooper J, Zijlstra A, Walker B, Quigley J, et al. The membrane-anchored serine protease, TMPRSS2, activates PAR-2 in prostate cancer cells. Biochem J 2005;388:967-72.
76. Mazzocca A, Coppari R, De Franco R, Cho J, Liebermann TA, Pinzani M, et al. A secreted form of ADAM9 promotes carcinoma invasion through tumor-stromal interactions. Cancer Res 2005;65:4728-38.
77. Hahn WC, Weinberg RA. Rules for making human tumor cells. N Engl J Med 2002;347:1593-1603.
78. Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nature Med 2004;10:789-799.
79. Duffy MJ. The biochemistry of metastasis. Adv Clin Chem 1996;32:135-166.
80. Poste G, Fidler IJ. The pathogenesis of cancer metastasis. Nature 1980;283:139-146.
81. Bernards R, Weinberg RA. A progression puzzle. Nature 2002;418:823.
82. Chambers AF, Tuck AB. Ras-responsive genes and tumor metastasis. Crit Rev Oncog 1993;4:95-114.
83. Yu D, Wang SS, Dulski KM, Tsai CM, Nicolson GL, Hung MC. c-erbB-2/neu overexpression enhances metastatic potential of human lung cancer cells by induction of metastasis-associated properties. Cancer Res 1994;54:3260-3266.
84. Myoui A, Nishimura R, Williams PJ, Hiraga T, Tamura D, Michigami T, et al. C-SRC tyrosine kinase activity is associated with tumor colonization in bone and lung in an animal model of human breast cancer metastasis. Cancer Res 2003;63:5028-5033.
85. Giehl K. Oncogenic Ras in tumour progression and metastasis. Biol. Chem. 2005; 386, 193-205.
86. Liao Y. et al Modulation of apoptosis, tumorigenesity and metastatic potential with antisense H-ras oligodeoxynucleotides in a high metastatic tumor model of hepatoma: LCI-D20. Hepatogastroenterology 2000; 47: 365-370.
87. Varghese HJ et al. Activated ras regulates the proliferation/apoptosis balance and early survival of developing micrometastases. Cancer Res. 2002; 62, 887-891.
88. Roger L, Gadea G, Roux P.Control of cell migration: a tumour suppressor function for p53? Biol Cell. 2006 Mar;98(3): 141-52.
89. Van den Steen PE, Dubois B, Nelissen I, Rudd PM, Dwek RA and Opdenakker G. Biochemistry and molecular biology of gelatinase B or matrix-metalloproteinase-9 (MMP-9). Crit. Rev. Biochem. Mol. Biol. 2002; 37: 375-536.
90. Yoon SO, Park SJ, Yun CH and Chung AS. Roles of matrix metalloproteinases in tumor metastasis and angiogenesis. J. Biochem. Mol. Biol. 2003; 36: 128-137.
91. Hofmann UB, Houben R, Brocker EB and Becker JC. Role of matrix metalloproteinases in melanoma cell invasion. Biochimie 2005; 87: 307-314 .
92. Ozaki I, Yamamoto K, Mizuta T, et al: Differential expression of laminin receptors in human hepatocellular carcinoma. Gut 1998; 43:837- 842.
93. Kleiner DE, Stetler-Stevenson WG: Matrix metalloproteinases and metastasis. Cancer Chemother Pharmacol 1999;43 Suppl:S42-S51.
94. Musso O, Theret N, Campion JP, et al: In situ detection of matrix metalloproteinase-2 (MMP2) and the metalloproteinase inhibitor TIMP2 transcripts in human primary hepatocellular carcinoma and in liver metastasis. J Hepatol 1997;26:593-605.
95. Yamamoto H, Itoh F, Sakamoto H, et al: Association of reduced cell adhesion regulator messenger RNA expression with tumor progression in human hepatocellular carcinoma. Int J Cancer 1997;74:251-254.
96. Harada T, Arii S, Mise M, et al. Membranetype matrix metalloproteinase-1(MT1-MTP) gene is overexpressed in highly invasive hepatocellular carcinomas. J Hepatol 1998;28:231-239.
97. Monvoisin A, Bisson C, Si-Tayeb K, et al. Involvement of matrix metalloproteinase type-3 in hepatocyte growth factor-induced invasion of human hepatocellular carcinoma cells. Int J Cancer 2002;97:157-162.
98. Carloni V, Mazzocca A, Pantaleo P, et al. The integrin, alpha6betal, is necessary for the matrix-dependent activation of FAK and MAP kinase and the migration of human hepatocarcinoma cells. Hepatology 2001;34:42-49.
99. Carloni V, Romanelli RG, Mercurio AM, et al. Knockout of alpha6 beta1-integrin expression reverses the transformed phenotype of hepatocarcinoma cells. Gastroenterology 115:433-442,1998;
100. Torimura T, Ueno T, Kin M, et al. Coordinated expression of integrin alpha6betal and laminin in hepatocellular carcinoma. Hum Pathol 1997;28:1131-1138.
101. Torimura T, Ueno T, Kin M, et al. Integrin alpha6betal plays a significant role in the attachment of hepatoma cells to laminin. J Hepatol 1999;31:734-740.
102. Yao M, Zhou XD, Zha XL, et al. Expression of the integrin alpha5 subunit and its mediated cell adhesion in hepatocellular carcinoma. J Cancer Res Clin Oncol 1997; 123:435-440.
103. Wood Jr S, Holyoke ED, Yardley JH. Mechanisms of metastasis production by blood borne cancer cells. Can Cancer Conf 1966;4:167-223.
104. Fidler IJ. The relationship of embolic homogeneity, number, size and viability to the incidence of experimental metastasis. Eur J Cancer 1973;9:223-7.
105. Ben-Baruch, A.Host microenvironment in breast cancer development: inflammatory cells, cytokines and chemokines in breast cancer progression: reciprocal tumour-microenvironment interactions. Breast Cancer Res 2003; 5: 31-36.
106. Kulbe H, Levinson NR, Balkwill F and Wilson JL. The chemokine network in cancer -much more than directing cell movement. Int. J. Dev. Biol. 2004; 48: 489-496.
107. Sica A, Schioppa T, Mantovani A and Allavena P. Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur. J. Cancer 2006; 42: 717-727.
108. O'Reilly MS et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 1994; 79: 315-328.
109. O'Reilly MS et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 1997;88: 277-285.