新肿瘤相关基因LAPTM4B在胆囊癌中的表达、临床病理和预后意义以及作用机制的研究
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摘要
背景:
胆囊癌来源于胆囊上皮,其发病隐匿,发展迅速,预后不良,严重威胁人类健康和生命安全。近年来我国胆囊癌的发病率呈增高趋势,更加凸现出对于其发生和发展进行深入研究的必要性。迄今,国内外学者研究发现胆囊癌细胞中多种肿瘤相关基因存在表达异常或突变,如K-ras、P53、P27~(kipl)、cyclin D1和β-catenin等。但是,近年在肝细胞癌中成功克隆的新肿瘤相关基因LAPTM4B(lysosome-associatedprotein transmembrane 4β)在胆囊癌中的表达及其临床、病理和预后意义,以及其相关作用机制尚不清楚。
目的:
本研究在相关前期文献报道的基础上首次探讨LAPTM4B基因在胆囊癌中的表达及其临床、病理和预后意义,并进一步着眼于该基因在胆囊癌中的作用及其相关分了机制,从而达到深化对胆囊癌发病和进展的了解及探索胆囊癌新的治疗靶点的目的。
方法:
第一部分LAPTM4B编码蛋白在胆囊癌中的表达及其临床病理和预后意义
免疫印迹:应用LAPTM4B-EC2多克隆抗体检测配对癌和癌旁组织LAPTM4B编码蛋白的表达。
免疫组织化学染色:应用特异性识别LAPTM4B-35蛋白的LAPTM4B-N_(1-99)多克隆抗体检测其表达,并与患者临床病理指标相联系。
生存分析:Kaplan-Meier法统计生存率,Log-rank检验进行单因素分析,Cox检验进行多因素分析。
第二部分LAPTM4B编码蛋白在胆囊癌细胞系GBC-SD中的表达
免疫细胞化学染色:应用特异性识别LAPTM4B-35蛋白的LAPTM4B-N_(1-99)多克降抗体检测其在胆囊癌细胞系GBC-SD中的表达。
免疫印迹:应用LAPTM4B-EC2多克隆抗体验证LAPTM4B编码蛋白在该细胞系中的表达。
第三部分LAPTM4B基因在胆囊癌细胞中的作用机制
质粒扩增及鉴定:大肠杆菌DH5α转化法扩增包含LAPTM4B完整开放阅读框架(ORF)的质粒pcDNA3-AE和空载质粒Mock(pcDNA3),核酸内切酶BamH1和EcoR1双酶切及测序鉴定。
质粒转染:以脂质体Lipofectamine~(TM) 2000将上述质粒瞬时转染至胆囊癌细胞系GBC-SD。
MTT检测:检测转染和亲本细胞增殖状况。
流式细胞术:检测转染和亲本细胞细胞周期和凋亡。
Transwell实验:检测转染和亲本细胞的迁移和侵袭。
过河实验:检测转染和亲本细胞的迁移。
免疫印迹:应用多种特异性抗体检测相关蛋白在转染和亲本细胞中的表达。
结果:
第一部分:
免疫印迹法检测的3对癌和癌旁组织中,LAPTM4B-35蛋白在2例患者的癌组织中阳性表达,而癌旁组织中均未见阳性条带。免疫组织化学染色发现LAPTM4B-35蛋白在57例(76%)胆囊癌患者的癌组织中阳性表达,其表达与肿瘤组织学类型、淋巴结累及、分期和分化程度以及患者预后密切相关。癌旁组织未见阳性染色。
第二部分:
免疫细胞化学染色显示LAPTM4B-35蛋白在胆囊癌细胞系GBC-SD中呈阳性表达,免疫印迹检测证实了这一发现但同时提示其表达较弱。
第三部分:
扩增后双酶切及测序鉴定表明扩增结果正确。
转染pcDNA3-AE后细胞呈现明显增殖加速和细胞周期演进、迁移和侵袭增强及表阿霉素所诱导细胞凋亡的显著减轻。这些表型出现的同时伴有c-myc、c-fos、c-jun、cyclin D1、cyclin E、MMP-2、MMP-9、uPA、Bcl-2和Bcl-xL表达上调及P16、P27、Bax、Bid、剪切型caspase-3和剪切型caspase-9表达下调。然而,转染Mock质粒后及亲本细胞则无类似效应。
结论:
LAPTM4B-35蛋白在大多数胆囊癌患者中表达阳性并具有重要的临床病理和预后意义。
LAPTM4B-35蛋白在胆囊癌细胞系GBC-SD中呈阳性表达。
LAPTM4B基因可促进胆囊癌细胞增殖、迁移和侵袭并可抑制其凋亡。这些作用可通过调节其下游多种基因的表达而实现。因此,LAPTM4B基因在胆囊癌中具有重要意义并有可能作为新的治疗靶点。
Background:
Gallbladder carcinoma,which originated in epithelium of the gallbladder,carried concealed onset,rapid progression and dismal prognosis,thus seriously threatening the human health and life safety.In recent years,the increasing tendency of gallbladder carcinoma incidence in China further presented the necessity for thorough investigations on its pathogenesis and development.So far,domestic and abroad researchers have found that abnormal expression and mutation of many tumor associated genes,such as K-ras, P53,P27~((kip1)),cyclin D1 andβ-catenin,existed in gallbladder carcinoma cells. Nevertheless,expression and its clinicopathological and prognostic significances,and relevant mechanisms of LAPTM4B(lysosome-associated protein transmembrane 4β),a novel tumor associated gene successfully cloned in hepatocellular carcinoma,remains unclear.
Objective:
The present study first,under the basis of previous relative literatures,explores the expression and clinical,pathological and prognostic significances,and further focusing on the effects and related molecular mechanisms of the gene on gallbladder carcinoma,in order to deepen the understanding on the pathogenesis and progression of gallbladder carcinoma and to probe into its new therapeutic targets.
Methods:
Part 1 Expression and clinicopathological and prognostic significances of LAPTM4B encoded proteins in gallbladder carcinoma
Western Blot:The expression of LAPTM4B encoded proteins is detected in paired cancerous and para-cancerous tissues,using polyclonal antibody LAPTM4B-EC2.
Immunohistochemical staining:The expression of LAPTM4B-35 protein is detected by polyclonal antibody LAPTM4B-N_(1-99),that specifically recognizes the protein,and is correlated with clinicopathological parameters of patients.
Survival analysis:Survival rates are calculated by Kaplan-Meier method.Log-rank and Cox regression tests are adopted for uni-and multi-variate analyses.
Part 2 Expression of LAPTM4B encoded proteins in gallbladder carcinoma cell line GBC-SD
Immunocytochemical staining:The expression of LAPTM4B-35 protein is detected by polyclonal antibody LAPTM4B-N_(1-99),that specifically recognizes the protein,in gallbladder carcinoma cell line GBC-SD.
Western Blot:The expression of LAPTM4B encoded proteins in gallbladder carcinoma cell line GBC-SD is confirmed using polyclonal antibody LAPTM4B-EC2.
Part 3 Mechanisms of LAPTM4B gene in gallbladder carcinoma cells
Plasmid amplification and identification:The plasmids pcDNA3-AE containing the complete open reading frame(ORF) of LAPTM4B and Mock(pcDNA3) are transformed into E.Coli DH5αand further amplified.The products are identified by digestion of endonucleases,BamH1 and EcoR1,and DNA sequencing.
Plasmid transfection:Aforementioned plasmids are trainsiently transfected into gallbladder carcinoma cell line GBC-SD by liposome Lipofectamine~(TM) 2000.
MTT assay:To detect proliferation of transfected and parent cells.
Flow cytometry:To detect cell cycle distribution and apoptosis of transfected and parent cells.
Transwell test:To detect migration and invasion of transfected and parent cells.
Crossing river test:To detect migration of transfected and parent cells.
Western Blot:To detect expression of related proteins in transfected and parent cells, using many kinds of specific antibody.
Results:
Part 1:
LAPTM4B-35 protein is positively expressed in cancerous tissues of 2 patients out of 3 pairs of cancerous and para-cancerous tissues detected by Western Blot,whereas no any band is observable in para-cancerous tissues.Immunohistochemical staining shows that LAPTM4B-35 protein is positively expressed in cancerous tissues of 57(76%) patients with gallbladder carcinoma.Besides,its expression is closely correlated with histological type,lymph node involvement,staging and differentiation of the tumor,as well as patient prognosis.No positive staining is found in para-cancerous tissues.
Part 2:
Immunocytochemical staining reveals that LAPTM4B-35 protein is positively expressed in gallbladder carcinoma cell line GBC-SD.Western blot detection confirms this finding but simultaneously shows that its expression is a bit weak.
Part 3:
Digestion of two endonucleases and DNA sequencing indicate correct amplification.
Cells transfected with pcDNA3-AE shows significantly accelerated proliferation and cell cycle progression,enhanced migration and invasion,and attenuated apoptosis induced by epirubicin.These phenotypes are accompanied by upregulated expression of c-myc,c-fos,c-jun,cyclin D1,cyclin E,MMP-2,MMP-9,uPA,Bcl-2 and Bcl-xL,and downregulated expression of P16,P27,Bax,Bid,cleaved caspase-3 and cleaved caspase-9.However,no similar effects are presented in cells transfected with the Mock plasmid and parent cells.
Conclusions:
LAPTM4B-35 protein is positively expressed in a majority of patients with gallbladder carcinoma and is of important clinicopathological and prognostic significances.
LAPTM4B-35 protein is positively expressed in gallbladder carcinoma cell line GBC-SD.
LAPTM4B gene promotes proliferation,migration and invasion,and inhibits apoptosis of gallbladder carcinoma cells.These effects are achieved via regulation of expression of multiple downstream genes.Therefore,LAPTM4B gene is of important implications in gallbladder carcinoma and may be a novel therapeutic target.
胆囊癌来源于胆囊上皮,其发病隐匿,发展迅速,预后不良,严重威胁人类健康和生命安全。近年来我国胆囊癌的发病率呈增高趋势,更加凸现出对于其发生和发展进行深入研究的必要性。迄今,国内外学者研究发现胆囊癌细胞中多种肿瘤相关基因存在表达异常或突变,如K-ras、P53、P27~(kipl)、cyclin D1和β-catenin等。但是,近年在肝细胞癌中成功克隆的新肿瘤相关基因LAPTM4B(lysosome-associatedprotein transmembrane 4β)在胆囊癌中的表达及其临床、病理和预后意义,以及其相关作用机制尚不清楚。
目的:
本研究在相关前期文献报道的基础上首次探讨LAPTM4B基因在胆囊癌中的表达及其临床、病理和预后意义,并进一步着眼于该基因在胆囊癌中的作用及其相关分了机制,从而达到深化对胆囊癌发病和进展的了解及探索胆囊癌新的治疗靶点的目的。
方法:
第一部分LAPTM4B编码蛋白在胆囊癌中的表达及其临床病理和预后意义
免疫印迹:应用LAPTM4B-EC2多克隆抗体检测配对癌和癌旁组织LAPTM4B编码蛋白的表达。
免疫组织化学染色:应用特异性识别LAPTM4B-35蛋白的LAPTM4B-N_(1-99)多克隆抗体检测其表达,并与患者临床病理指标相联系。
生存分析:Kaplan-Meier法统计生存率,Log-rank检验进行单因素分析,Cox检验进行多因素分析。
第二部分LAPTM4B编码蛋白在胆囊癌细胞系GBC-SD中的表达
免疫细胞化学染色:应用特异性识别LAPTM4B-35蛋白的LAPTM4B-N_(1-99)多克降抗体检测其在胆囊癌细胞系GBC-SD中的表达。
免疫印迹:应用LAPTM4B-EC2多克隆抗体验证LAPTM4B编码蛋白在该细胞系中的表达。
第三部分LAPTM4B基因在胆囊癌细胞中的作用机制
质粒扩增及鉴定:大肠杆菌DH5α转化法扩增包含LAPTM4B完整开放阅读框架(ORF)的质粒pcDNA3-AE和空载质粒Mock(pcDNA3),核酸内切酶BamH1和EcoR1双酶切及测序鉴定。
质粒转染:以脂质体Lipofectamine~(TM) 2000将上述质粒瞬时转染至胆囊癌细胞系GBC-SD。
MTT检测:检测转染和亲本细胞增殖状况。
流式细胞术:检测转染和亲本细胞细胞周期和凋亡。
Transwell实验:检测转染和亲本细胞的迁移和侵袭。
过河实验:检测转染和亲本细胞的迁移。
免疫印迹:应用多种特异性抗体检测相关蛋白在转染和亲本细胞中的表达。
结果:
第一部分:
免疫印迹法检测的3对癌和癌旁组织中,LAPTM4B-35蛋白在2例患者的癌组织中阳性表达,而癌旁组织中均未见阳性条带。免疫组织化学染色发现LAPTM4B-35蛋白在57例(76%)胆囊癌患者的癌组织中阳性表达,其表达与肿瘤组织学类型、淋巴结累及、分期和分化程度以及患者预后密切相关。癌旁组织未见阳性染色。
第二部分:
免疫细胞化学染色显示LAPTM4B-35蛋白在胆囊癌细胞系GBC-SD中呈阳性表达,免疫印迹检测证实了这一发现但同时提示其表达较弱。
第三部分:
扩增后双酶切及测序鉴定表明扩增结果正确。
转染pcDNA3-AE后细胞呈现明显增殖加速和细胞周期演进、迁移和侵袭增强及表阿霉素所诱导细胞凋亡的显著减轻。这些表型出现的同时伴有c-myc、c-fos、c-jun、cyclin D1、cyclin E、MMP-2、MMP-9、uPA、Bcl-2和Bcl-xL表达上调及P16、P27、Bax、Bid、剪切型caspase-3和剪切型caspase-9表达下调。然而,转染Mock质粒后及亲本细胞则无类似效应。
结论:
LAPTM4B-35蛋白在大多数胆囊癌患者中表达阳性并具有重要的临床病理和预后意义。
LAPTM4B-35蛋白在胆囊癌细胞系GBC-SD中呈阳性表达。
LAPTM4B基因可促进胆囊癌细胞增殖、迁移和侵袭并可抑制其凋亡。这些作用可通过调节其下游多种基因的表达而实现。因此,LAPTM4B基因在胆囊癌中具有重要意义并有可能作为新的治疗靶点。
Background:
Gallbladder carcinoma,which originated in epithelium of the gallbladder,carried concealed onset,rapid progression and dismal prognosis,thus seriously threatening the human health and life safety.In recent years,the increasing tendency of gallbladder carcinoma incidence in China further presented the necessity for thorough investigations on its pathogenesis and development.So far,domestic and abroad researchers have found that abnormal expression and mutation of many tumor associated genes,such as K-ras, P53,P27~((kip1)),cyclin D1 andβ-catenin,existed in gallbladder carcinoma cells. Nevertheless,expression and its clinicopathological and prognostic significances,and relevant mechanisms of LAPTM4B(lysosome-associated protein transmembrane 4β),a novel tumor associated gene successfully cloned in hepatocellular carcinoma,remains unclear.
Objective:
The present study first,under the basis of previous relative literatures,explores the expression and clinical,pathological and prognostic significances,and further focusing on the effects and related molecular mechanisms of the gene on gallbladder carcinoma,in order to deepen the understanding on the pathogenesis and progression of gallbladder carcinoma and to probe into its new therapeutic targets.
Methods:
Part 1 Expression and clinicopathological and prognostic significances of LAPTM4B encoded proteins in gallbladder carcinoma
Western Blot:The expression of LAPTM4B encoded proteins is detected in paired cancerous and para-cancerous tissues,using polyclonal antibody LAPTM4B-EC2.
Immunohistochemical staining:The expression of LAPTM4B-35 protein is detected by polyclonal antibody LAPTM4B-N_(1-99),that specifically recognizes the protein,and is correlated with clinicopathological parameters of patients.
Survival analysis:Survival rates are calculated by Kaplan-Meier method.Log-rank and Cox regression tests are adopted for uni-and multi-variate analyses.
Part 2 Expression of LAPTM4B encoded proteins in gallbladder carcinoma cell line GBC-SD
Immunocytochemical staining:The expression of LAPTM4B-35 protein is detected by polyclonal antibody LAPTM4B-N_(1-99),that specifically recognizes the protein,in gallbladder carcinoma cell line GBC-SD.
Western Blot:The expression of LAPTM4B encoded proteins in gallbladder carcinoma cell line GBC-SD is confirmed using polyclonal antibody LAPTM4B-EC2.
Part 3 Mechanisms of LAPTM4B gene in gallbladder carcinoma cells
Plasmid amplification and identification:The plasmids pcDNA3-AE containing the complete open reading frame(ORF) of LAPTM4B and Mock(pcDNA3) are transformed into E.Coli DH5αand further amplified.The products are identified by digestion of endonucleases,BamH1 and EcoR1,and DNA sequencing.
Plasmid transfection:Aforementioned plasmids are trainsiently transfected into gallbladder carcinoma cell line GBC-SD by liposome Lipofectamine~(TM) 2000.
MTT assay:To detect proliferation of transfected and parent cells.
Flow cytometry:To detect cell cycle distribution and apoptosis of transfected and parent cells.
Transwell test:To detect migration and invasion of transfected and parent cells.
Crossing river test:To detect migration of transfected and parent cells.
Western Blot:To detect expression of related proteins in transfected and parent cells, using many kinds of specific antibody.
Results:
Part 1:
LAPTM4B-35 protein is positively expressed in cancerous tissues of 2 patients out of 3 pairs of cancerous and para-cancerous tissues detected by Western Blot,whereas no any band is observable in para-cancerous tissues.Immunohistochemical staining shows that LAPTM4B-35 protein is positively expressed in cancerous tissues of 57(76%) patients with gallbladder carcinoma.Besides,its expression is closely correlated with histological type,lymph node involvement,staging and differentiation of the tumor,as well as patient prognosis.No positive staining is found in para-cancerous tissues.
Part 2:
Immunocytochemical staining reveals that LAPTM4B-35 protein is positively expressed in gallbladder carcinoma cell line GBC-SD.Western blot detection confirms this finding but simultaneously shows that its expression is a bit weak.
Part 3:
Digestion of two endonucleases and DNA sequencing indicate correct amplification.
Cells transfected with pcDNA3-AE shows significantly accelerated proliferation and cell cycle progression,enhanced migration and invasion,and attenuated apoptosis induced by epirubicin.These phenotypes are accompanied by upregulated expression of c-myc,c-fos,c-jun,cyclin D1,cyclin E,MMP-2,MMP-9,uPA,Bcl-2 and Bcl-xL,and downregulated expression of P16,P27,Bax,Bid,cleaved caspase-3 and cleaved caspase-9.However,no similar effects are presented in cells transfected with the Mock plasmid and parent cells.
Conclusions:
LAPTM4B-35 protein is positively expressed in a majority of patients with gallbladder carcinoma and is of important clinicopathological and prognostic significances.
LAPTM4B-35 protein is positively expressed in gallbladder carcinoma cell line GBC-SD.
LAPTM4B gene promotes proliferation,migration and invasion,and inhibits apoptosis of gallbladder carcinoma cells.These effects are achieved via regulation of expression of multiple downstream genes.Therefore,LAPTM4B gene is of important implications in gallbladder carcinoma and may be a novel therapeutic target.
引文
1. Kapoor VK. Gallbladder cancer: a global perspective. J Surg Oncol, 2006, 93:607-609.
2. Lazcano-Ponce EC, Miquel JF, Munoz N, et al. Epidemiology and molecular pathology of gallbladder cancer. CA Cancer J Clin, 2001, 51: 349-364.
3. Pandey M. Risk factors for gallbladder cancer: A reappraisal. Eur J Cancer Prev,2003,12: 15-24.
4. Nandakumar A, Gupta PC, Gangadharan P, et al. Geographic pathology revisited: Development of an atlas of cancer in India. Int J Cancer, 2005, 116: 740-754.
5. Misra S, Chaturvedi A, Misra NC, et al. Carcinoma of the gallbladder. Lancet Oncol,2003,4:167-176.
6. Lowen fels AB, lindstrom CG, Conway MJ. Gall stones and risk of gall bladder cancer. JNCI, 1985, 75: 77-80.
7. Arundhati Rai, Mohapatra SC, Shukla HS. A review of association of dietary factor in gall bladder cancer. IJC, 2004, 75: 368-370.
8. Chao TC, Jan YY, Chen MF. Primary carcinoma of the gall bladder associated with anomalous pancreatio biliary ductal junction. J Clin Gastoenterol, 1995, 21: 306-309.
9. Kumar S, Kumar S, Kumar S. Infection as a risk factor for gallbladder cancer. J Surg Oncol, 2006, 93: 633-639.
10. Carriaga MT, Henson DE. Liver, gallbladder, extrahepatic bile ducts, and pancreas.Cancer, 1995,75: 171-190.
11. Cubertafond P, Gainant A, Cucchiaro G Surgical treatment of 724 carcinomas of the gallbladder. Results of the French Surgical Association Survey. Ann Surg, 1994, 219:275-280.
12. Wilkinson DS. Carcinoma of the gall-bladder: an experience and review of the literature. Aust NZ J Surg, 1995, 65: 724-727.
13. Wakai T, Shirai Y, Yokoyama N, et al. Early gallbladder carcinoma does not warrant radical resection. Br J Surg, 2001, 88: 675-678.
14. Ito H, Matros E, Brooks DC, et al. Treatment outcomes associated with surgery for gallbladder cancer:a 20-year experience.J Gastrointest Surg,2004,8:183-190.
15.Hsing AW,Gao YT,Devesa SS,et al.Rising incidence of biliary tract cancers in Shanghai,China.Int J Cancer,1998,75:368-370.
16.张微,项永兵,刘振伟,等.1973-1999年上海市区老年人恶性肿瘤发病趋势分析。中华老年医学杂志,2005,24:701-704.
17.马新源,汪祥辉,雷通海,等.嘉善县恶性肿瘤发病率及动态研究。中国肿瘤,2001,10:378-380.
18.石景森,杨毅军,赵凤林,等.原发性胆囊癌44年诊治的临床回顾。外科理论与实践,2001,6:137-141.
19.Zou S,Zhang L,Zen G,et al.Clinical epidemiologic characteristics of 430 cases of gallbladder cancer.Chin Med J,1998,111:391-393.
20.Hsing AW,Gao YT,Han TQ,et al.Gallstones and the risk of biliary tract cancer:a population-based study in China.Br J Cancer,2007,97:1577-1582.
21.Malats N,Porta M,Pinol JL,et al.Ki-ras mutations as a prognostic factor in extrahepatic bile system cancer.J Clin Oncol,1995,13:1679-1686.
22.Hanada K,Tsuchida A,Iwao T,et al.Gene mutations of K-ras in gallbladder mucosa and gallbladder carcinoma with an anomalous junction of the pancreaticobiliary duct.Am J Gastroenterol,1999,94:1638-1642.
23.Suzuki T,Takano Y,Kakita A,et al.An immunohistochemical and molecular biological study of c-erbB-2 amplification and prognostic relevance in gallbladder cancer.Pathol Res Pract,1993,189:283-292.
24.Nakazawa K,Dobashi Y,Suzuki S,et al.Amplification and overexpression of c-erbB-2,epidermal growth factor receptor,and c-met in biliary tract cancers.J Pathol,2005,206:356-365.
25.Itoi T,Shinohara Y,Takeda K,et al.Nuclear cyclin D1 overexpression is a critical event associated with cell proliferation and invasive growth in gallbladder carcinogenesis.J Gastroenterol,2000,35:142-149.
26.Hui AM,Li X,Shi YZ,et al.Cyclin D1 overexpression is a critical event in gallbladder carcinogenesis and independently predicts decreased survival for patients with gallbladder carcinoma.Clin Cancer Res,2000,6:4272-4277.
27.Hanada K,Itoh M,Fujii K,et al.TP53 mutations in stage Ⅰ gallbladder carcinoma with special attention to growth patterns.Eur J Cancer,1997,33:1136-1140.
28.Chang HJ,Yoo BC,Kim SW,et al.Significance of PML and p53 protein as molecular prognostic markers of gallbladder carcinomas.Pathol Oncol Res,2007,13:326-335.
29.Parwani AV,Geradts J,Caspers E,et al.Immunohistochemical and genetic analysis of non-small cell and small cell gallbladder carcinoma and their precursor lesions.Mod Pathol,2003,16:299-308.
30.Ueki T,Hsing AW,Gao YT,et al.Alterations of p16 and prognosis in biliary tract cancers from a population-based study in China.Clin Cancer Res,2004,10:1717-1725.
31.Shi YZ,Hui AM,Li X,et al.Overexpression of retinoblastoma protein predicts decreased survival and correlates with loss of p16INK4 protein in gallbladder carcinomas.Clin Cancer Res,2000,6:4096-4100.
32.黄英,郑长黎.原发性胆囊癌中PTEN和P53基因表达的研究。中国癌症杂志,2006,16:547-550.
33.Takahashi T,Shivapurkar N,Riquelme E,et al.Aberrant promoter hypermethylation of multiple genes in gallbladder carcinoma and chronic cholecystitis.Clin Cancer Res,2004,10:6126-6133.
34.Roa JC,Anabal6n L,Roa I,et al.Promoter methylation profile in gallbladder cancer.J Gastroenterol,2006,41:269-275.
35.Mikami T,Yanagisawa N,Baba H,et al.Association of Bcl-2 protein expression with gallbladder carcinoma differentiation and progression and its relation to apoptosis.Cancer,1999,85:318-325.
36.Yanagisawa N,Mikami T,Mitomi H,et al.CD44 variant overexpression in gallbladder carcinoma associated with tumor dedifferentiation.Cancer,2001,91:408-416.
37.刘军建,张杰,张宁,等.用荧光差异显示法分离新的肝细胞癌相关基因。北京医科大学学报,2000,32:411-414.
38.Liu J,Zhou RL,Zhang N,et al.Biological function of a novel gene overexprcsscd in human hepatocellular carcinoma.Chin Med J,2000,113:881-885.
39.Shao GZ,Zhou RL,Zhang QY,et al.Molecular cloning and characterization of LAPTM4B,a novel gene upregulated in hepatocellular carcinoma.Oncogene,2003,22:5060-5069.
40.邵根泽.人肝细胞癌相关基因LAPTM4B的克隆及其功能研究。北京大学医学部博士学位论文,2003.
41.邓丽娟,张青云,刘波,等.LAPTM4B基因多态性与肺癌易感性的关系。北京大学学报(医学版),2005,37:302-305.
42.Liu Y,Zhang QY,Qian N,et al.Relationship between LAPTM4B gene polymorphism and susceptibility of gastric cancer.Ann Oncol,2007,18:311-316.
43.Cheng XJ,Xu W,Zhang QY,et al.Relationship between LAPTM4B gene polymorphism and susceptibility of colorectal and esophageal cancers.Ann Oncol,2008,19:527-532.
44.刘歆荣,周柔丽,张青云,等.人肝癌相关新基因编码产物LAPTM4B的鉴定及其生物学特性。北京大学学报(医学版),2003,35:340-347.
45.Liu XR,Zhou RL,Zhang QY,et al.Structure analysis and expressions of a novel tetratransmembrane protein,lysosoma-associated protein transmembrane 4 beta associated with hepatocellular carcinoma.World J Gastroenterol,2004,10:1555-1559.
46.何静,邵根泽,周柔丽.肝癌中高表达的新基因LAPTM4B对细胞增殖及成瘤性的影响。北京大学学报(医学版),2003,35:348-352.
47.Peng C,Zhou RL,Shao GZ,et al.Expression of lysosome-associated protein transmembrane 4B-35 in cancer and its correlation with the differentiation status of hepatocellular carcinoma.World J Gastroenterol,2005,11:2704-2708.
48.Kasper G,Vogel A,Klaman I,et al.The human LAPTM4b transcript is upregulated in various types of solid tumours and seems to play a dual functional role during tumour progression.Cancer Lett,2005,224:93-103.
49.Morris DG,Musat M,Czirjak S,et al.Differential gene expression in pituitary adenomas by oligonucleotide array analysis.Eur J Endocrinol,2005,153:143-151.
50.Nevin JE,Moran TJ,Kay S,et al.Carcinoma of the gallbladder:staging,treatment,and prognosis.Cancer,1976,37:141-148.
51. Hogue DL, Kerby L, Ling V. A mammalian lysosomal membrane protein confers multidrug resistance upon expression in Saccharomyces cerevisiae. J Biol Chem,1999,274: 12877-12882.
52. Sanz-Altamira PM, Ferrante K, Jenkins RL, et al. A phase II trial of 5-fluorouracil,leucovorin, and carboplatin in patients with unresectable biliary tree carcinoma.Cancer, 1998,82:2321-2325.
53. Wakai T, Shirai Y, Yokoyama N, et al. Depth of subserosal invasion predicts long-term survival after resection in patients with T2 gallbladder carcinoma. Ann Surg Oncol, 2003, 10: 447-454.
54. Nakata T, Kobayashi A, Miwa S, et al. Impact of tumor spread to the cystic duct on the prognosis of patients with gallbladder carcinoma. World J Surg 2007, 31:155-161.
55. Wakabayashi H, Ishimura K, Hashimoto N, et al. Analysis of prognostic factors after surgery for stage III and IV gallbladder cancer. Eur J Surg Oncol, 2004, 30: 842-846.
56. Noshiro H, Chijiiwa K, Yamaguchi K, et al. Factors affecting surgical outcome for gallbladder carcinoma. Hepatogastroenterology, 2003, 50: 939-944.
57. Aramaki M, Matsumoto T, Shibata K, et al. Factors influencing recurrence after surgical treatment for T2 gallbladder carcinoma. Hepatogastroenterology, 2004, 51:1609-1611.
58. Kai M, Chijiiwa K, Ohuchida J, et al. A curative resection improves the postoperative survival rate even in patients with advanced gallbladder carcinoma. J Gastrointest Surg, 2007, 11: 1025-1032.
59. Sasaki E, Nagino M, Ebata T, et al. Immunohistochemically demonstrated lymph node micrometastasis and prognosis in patients with gallbladder carcinoma. Ann Surg, 2006, 244: 99-105.
60. Hui AM, Li X, Shi YZ, et al. p27(Kip1) expression in normal epithelia, precancerous lesions, and carcinomas of the gallbladder: association with cancer progression and prognosis. Hepatology, 2000, 31: 1068-1072.
61. Varga M, Obrist P, Schneeberger S, et al. Overexpression of epithelial cell adhesion molecule antigen in gallbladder carcinoma is an independent marker for poor survival. Clin Cancer Res, 2004, 10: 3131-3136.
62.Li SH,Li CF,Sung MT,et al.Skp2 is an independent prognosticator of gallbladder carcinoma among p27(Kip1)-interacting cell cycle regulators:an immunohistochemical study of 62 cases by tissue microarray.Mod Pathol,2007,20:497-507.
63.Jiang W,Kahn SM,Zhou P,et al.Overexpression of cyclin D1 in rat fibroblasts causes abnormalities in growth control,cell cycle progression and gene expression.Oncogene,1993,8:3447-3457.
64.Polyak K,Lee M,Erdjement-Bromage H,et al.Cloning of p27~(Kipl),a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals.Cell,1994,79:59-66.
65.Sutterluty H,Chatelain E,Marti A,et al.p45~(Skp2) promotes p27~(Kipl) degradation and induces S phase in quiescent cells.Nat Cell Biol,1999,1:207-214.
66.Koyama S,Yoshioka T,Mizushima A,et al.Establishment of a cell line(G-415)from a human gallbladder carcinoma.Jpn J Cancer Res,1980,71:574-575.
67.Knuth A,Gabbert H,Dippold W,et al.Biliary adenocarcinoma:characterisation of three new human tumor cell lines.J Hepatol,1985,1:579-596.
68.Nakano S,Tatsumoto T,Esaki T,et al.Characterization of a newly established human gallbladder carcinoma cell line.In Vitro Cell Dev Biol Anim,1994,30A:729-732.
69.Nishida T,Iwasaki H,Johzaki H,et al.A human gallbladder signet ring cell carcinoma cell line.Pathol Int,1997,47:368-376.
70.刘博,王古民,吴小鹏,等.人胆囊癌细胞系GBC-SD的建立。山东医科大学学报,2000,38:332-333.
71.刘博,王古民,吴小鹏,等.胆囊癌细胞系GBC-SD的牛物学行为研究。外科理论与实践,2001,6:146-148.
72.李东华,王古民,刘军,等.人胆囊癌细胞系GBC-SD的多药耐药机制。中华实验外科杂志,2003,20:995-997.
73.乌新林,王古民,马道新,等.人胆囊癌细胞系GBC-SD p53基因突变的研究。山东大学学报·医学版,2005,43:66-68.
74.乌新林,施琳,罗力,等.稳定表达外源野生型p53基因人胆囊癌细胞系的建 立和鉴定。内蒙古医学院学报,2005,27:189-192.
75.乌新林,王占民,杨凤辉,等.野生型p53基因对人胆囊癌细胞生长及致瘤性的抑制作用。中国肿瘤生物治疗杂志,2005,12:266-271.
76.刘颖斌,何小伟,王建伟,等.胆囊癌肝转移模型的建立和高转移细胞亚群的筛选。中华医学杂志,2006,86:2117-2121.
77.Chang XZ,Wang ZM,Yu JM,et al.Isolation of a human gallbladder cancer cell clone with high invasive phenotype in vitro and metastatic potential in orthotopic model and inhibition of its invasiveness by heparanase antisense oligodeoxynucleotides.Clin Exp Metastasis,2007,24:25-38.
78.冯立民,王建立,乌新林,等.单独及联合转染survivin和bcl-2反义寡核苷酸诱导胆囊癌细胞凋亡的研究。中国肿瘤生物治疗杂志,2004,11:248-251.
79.Ai Z,Lu W,Ton S,et al.Arsenic trioxide-mediated growth inhibition in gallbladder carcinoma cells via down-regulation of Cyclin D1 transcription mediated by Sp1transcription factor.Biochem Biophys Res Commun,2007,360:684-689.
80.范跃祖,傅锦业,赵泽明,等.去甲斑蝥素对人胆囊癌GBC-SD细胞系增殖及侵袭的影响。中华肿瘤杂志,2004,26:271-274.
81.Oster SK,Ho CS,Soucie EL,et al.The myc oncogene:Marvelously complex.Adv Cancer Res,2002,84:81-154.
82.Milde-Langosch K.The Fos family of transcription factors and their role in tumourigenesis.Eur J Cancer,2005,41:2449-2461.
83.van Dam H,Castellazzi M.Distinct roles of Jun:Fos and Jun:ATF dimers in oncogenesis.Oncogene,2001,20:2453-2464.
84.Jochum W,Passegue E,Wagner EF.AP-1 in mouse development and tumourigenesis.Oncogene,2001,20:2401-2412.
85.Shaulian E,Karin M.AP-1 in cell proliferation and survival.Oncogene,2001,20:2390-2400.
86.Shaulian E,Karin M.AP-1 as a regulator of cell life and death.Nat Cell Biol,2002,4:E131-E136.
87.Jiang W,Kahn SM,Zhou P,et al.Overexpression of cyclin D1 in rat fibroblasts causes abnormalities in growth control,cell cycle progression and gene expression. Oncogene,1993,8:3447-3457.
88.Ohtsubo M,Roberts JM.Cyclin-dependent regulation of G1 in mammalian fibroblasts.Science,1993,259:1908-1912.
89.孙丽,张青云.人肝癌相关新基因LAPTM4B研究进展。世界华人消化杂志,2006,14:1805-1809.
90.Sherr CJ.G1 phase progression:Cycling on cue.Cell,1994,79:551-555.
91.Malumbres M,Barbacid M.Mammalian cyclin-dependent kinases.Trends Biochem Sci,2005,30:630-641.
92.Cánepa ET,Scassa ME,Ceruti JM,et al.INK4 proteins,a family of mammalian CDK inhibitors with novel biological functions.IUBMB Life,2007,59:419-426.
93.Gartel AL,Shchors K.Mechanisms of c-myc-mediated transcriptional repression of growth arrest genes.Exp Cell Res,2003,283:17-21.
94.Mook OR,Frederiks WM,Van Noorden CJ.The role of gelatinases in colorectal cancer progression and metastasis.Biochim Biophys Acta,2004,1705:69-89.
95.Nakajima M,Chop AM.Tumor invasion and extracellular matrix degradative enzyme:regulation of activity by organ factors.Semin Cancer Biol,1991,2:115-127.
96.Shah V,Kumar S,Zirvi KA.Metastasis of human colon tumor cells in vivo:correlation with the overexpression of plasminogen activators and 72 kDa gelatinase.In Vivo,1994,8:321-326.
97.Hyuga S,Nishikawa Y,Sakata K,et al.Autocrine factor enhancing the secretion of M(r) 95,000 gelatinase(matrix metalloproteinase 9) in serum-free medium conditioned with murine metastatic colon carcinoma cells.Cancer Res,1994,54:3611-3616.
98.Jankun J,Merrick HW,Goldblatt PJ.Expression and localization of elements of the plasminogen activation system in benign breast disease and breast cancers.J Cell Biochem,1993,53:135-144.
99.Yan C,Boyd DD.Regulation of matrix metalloproteinase gene expression.J Cell Physiol,2007,211:19-26.
100.Qin H,Sun Y,Benveniste EN.The transcription factors Sp1,Sp3,and AP-2 are required for constitutive matrix metalloproteinase-2 gene expression in astroglioma cells. J Biol Chem, 1999, 274: 29130-29137.
101.Mazzieri R, Masiero L, Zanetta L, et al. Control of type IV collagenase activity by components of the urokinase-plasmin system: a regulatory mechanism with cell-bound reactants. EMBOJ, 1997, 16: 2319-2332.
102.Liu GY, Frank N, Bartsch H, et al. Induction of apoptosis by thiuramdisulfides, the reactive metabolites of dithiocarbamates, through coordinative modulation of NFkappaB, c-fos/c-jun, and p53 proteins. Mol Carcinog, 1998, 22: 235-246.
103.Takeuchi K, Motoda Y, Ito F. Role of transcription factor activator protein 1 (AP1) in epidermal growth factor-mediated protection against apoptosis induced by a DNA-damaging agent. FEBS J, 2006, 273: 3743-3755.
104.Hemann MT, Lowe SW. The p53-Bcl-2 connection. Cell Death Differ, 2006, 13:1256-1259.
105.Pelengaris S, Khan M. The many faces of c-MYC. Arch Biochem Biophys, 2003,416: 129-136.
106.Conzen SD, Gottlob K, Kandel ES, et al. Induction of cell cycle progression and acceleration of apoptosis are two separable functions of c-Myc: transrepression correlates with acceleration of apoptosis. Mol Cell Biol, 2000, 20: 6008-6018.
1.Kapoor VK.Gallbladder cancer:a global perspective.J Surg Oncol,2006,93:607-609.
2.Lazcano-Ponce EC,Miquel JF,Munoz N,et al.Epidemiology and molecular pathology of gallbladder cancer.CA Cancer J Clin,2001,51:349-364.
3.Pandey M.Risk factors for gallbladder cancer:A reappraisal.Eur J Cancer Prey,2003,12:15-24.
4.Nandakumar A,Gupta PC,Gangadharan P,et al.Geographic pathology revisited:Development of an atlas of cancer in India.Int J Cancer,2005,116:740-754.
5.Misra S,Chaturvedi A,Misra NC,et al.Carcinoma of the gallbladder.Lancet Oncol,2003,4:167-176.
6.Hsing AW,Gao YT,Devesa SS,et al.Rising incidence of biliary tract cancers in Shanghai,China.Int J Cancer,1998,75:368-370.
7.张薇,项永兵,刘振伟,等.1973-1999年上海市区老年人恶性肿瘤发病趋势分析。中华老年医学杂志,2005,24:701-704.
8.马新源,汪祥辉,雷通海,等.嘉善县恶性肿瘤发病率及动态研究。中国肿瘤,2001,10:378-380.
9.石景森,杨毅军,赵凤林,等.原发性胆囊癌44年诊治的临床回顾。外科理论与实践,2001,6:137-141.
10.Carriaga MT,Henson DE.Liver,gallbladder,extrahepatic bile ducts,and pancreas.Cancer,1995,75:171-190.
11.Cubertafond P,Gainant A,Cucchiaro G.Surgical treatment of 724 carcinomas of the gallbladder.Results of the French Surgical Association Survey.Ann Surg,1994,219:275-280.
12.Wilkinson DS.Carcinoma of the gall-bladder:an experience and review of the literature.Aust NZ J Surg,1995,65:724-727.
13.Wakai T,Shirai Y,Yokoyama N,et al.Early gallbladder carcinoma does not warrant radical resection.Br J Surg,2001,88:675-678.
14.Ito H,Matros E,Brooks DC,et al.Treatment outcomes associated with surgery for gallbladder cancer:a 20-year experience.J Gastrointest Surg,2004,8:183-190.
15.Lowen fels AB,lindstrom CG,Conway MJ.Gall stones and risk of gall bladder cancer.JNCI,1985,75:77-80.
16.Arundhati Rai,Mohapatra SC,Shukla HS.A review of association of dietary factor in gall bladder cancer.IJC,2004,41:147-152.
17.Kumar S,Kumar S,Kumar S.Infection as a risk factor for gallbladder cancer.J Surg Oncol,2006,93:633-639.
18.顾健人.癌基因、抗癌基因和哺乳动物细胞摹因表达调控。基因分子生物学研究进展,上海:上海科学技术出版社,53-63.
19.Shields JM,Pruitt K,McFall A,et al.Understanding Ras:"it ain't over 'til it's over".Trends Cell Biol,2000,10:147-154.
20.Tada M,Yokosuka O,Omata M,et al.Analysis of ras gene mutations in biliary and pancreatic tumors by polymerase chain reaction and direct sequencing.Cancer,1990,66:930-935.
21.Imai M,Hoshi T,Ogawa T.K-ras codon 12 mutations in biliary tract tumors detected by polymerase chain reaction denaturing gradient gel electrophoresis.Cancer,1994,73:2727-2733.
22.Watanabe M,Asaka M,Tanaka J,et al.Point mutation of K-ras gene codon 12 in biliary tract tumors.Gastroenterology,1994,107:1147-1153.
23.Malats N,Porta M,Pinol JL,et al.Ki-ras mutations as a prognostic factor in extrahepatic bile system cancer.J Clin Oncol,1995,13:1679-1686.
24.Ajiki T,Fujimori T,Onoyama H,et al.K-ras gene mutation in gallbladder carcinomas and dysplasia.Gut,1996,38:426-429.
25.Hanada K,Tsuchida A,Iwao T,et al.Gene mutations of K-ras in gallbladder mucosa and gallbladder carcinoma with an anomalous junction of the pancreaticobiliary duct.Am J Gastroenterol,1999,94:1638-1642.
26.Kim SW,Her KH,Jang JY,et al.K-ras oncogene mutation in cancer and precancerous lesions of the gallbladder.J Surg Oncol,2000,75:246-251.
27.Lee CS.Ras p21 protein immunoreactivity and its relationship to p53 expression and prognosis in gallbladder and extrahepatic biliary carcinoma.Eur J Surg Oncol,1997,23:233-237.
28.姚宏,邢惠清,赵玛丽,等.P2lras在胆囊癌前病变和胆囊癌细胞表达的定量研究。临床肝胆病杂志,1996,12:200-202.
29.Dammann R,Li C,Yoon JH,et al.Epigenetic inactivation of a RAS association domain family protein from the lung tumor suppressor locus 3p21.3.Nat Genet,2000,25:315-319.
30.Vavvas D,Li X,Avruch J,et al.Identification of Norel as a potential Ras effector.J Biol Chem,1998,273:5439-5442.
31.Dreijerink K,Braga E,Kuzmin I,et al.The candidate tumor suppressor gene,RASSF1A,from human chromosome 3p21.3 is involved in kidney tumorigenesis.Proc Natl Acad Sci USA,2001,98:7504-7509.
32.van Engeland M,Roemen GM,Brink M,et al.K-ras mutations and RASSF1A promoter methylation in colorectal cancer.Oncogene,2002,21:3792-3795.
33.Takahashi T,Shivapurkar N,Riquelme E,et al.Aberrant promoter hypermethylation of multiple genes in gallbladder carcinoma and chronic cholecystitis.Clin Cancer Res,2004,10:6126-6133.
34.Riquelme E,Tang M,Baez S,et al.Frequent epigenetic inactivation of chromosome 3p candidate tumor suppressor genes in gallbladder carcinoma.Cancer Lett,2007,250:100-106.
35.Adhikary S,Eilers M.Transcriptional regulation and transformation by Myc proteins.Nature Rev Mol Cell,2005,6:635-645.
36.Nesbit CE,Tersak JM,Prochownik EV.Myc oncogenes and human neoplastic disease.Oncogene,1999,18:3004-3016.
37.Lee W,Mitchell P,Tjian R.Purified transcription factor AP-1 interacts with TPA-inducible enhancer elements.Cell,1987,49:741-752.
38.Chiu R,Boyle WJ,Meek J,et al.The c-Fos protein interacts with c-Jun/AP-1 to stimulate transcription of AP-1 responsive genes.Cell,1988,54:541-552.
39.Curran T,Franza BR Jr.Fos and Jun:the AP-1 connection.Cell,1988,55:395-397.
40.Milde-Langosch K.The Fos family of transcription factors and their role in tumourigenesis.Eur J Cancer,2005,41:2449-2461.
41.Yukawa M,Fujimori T,Hirayama D,et al.Expression of oncogene products and growth factors in early gallbladder cancer,advanced gallbladder cancer,and chronic cholecystitis.Hum Pathol,1993,24:37-40.
42.Lee CS.Differences in c-fos gene product expression in cancers of the gall-bladder and biliary tract.Pathol Int,1996,46:771-776.
43.Asano T,Shoda J,Ueda T,et al.Expressions of cyclooxygenase-2 and prostaglandin E-receptors in carcinoma of the gallbladder:crucial role of arachidonate metabolism in tumor growth and progression.Clin Cancer Res,2002,8:1157-1167.
44.Semba K,Kamata N,Toyoshima K,et al.A v-erbB-related protooncogene,c-erbB-2,is distinct from the c-erbB-1/epidermal growth factor-receptor gene and is amplified in a human salivary gland adenocarcinoma.Proc Natl Acad Sci U S A,1985,82:6497-6501.
45.Moasser MM.The oncogene HER2:its signaling and transforming functions and its role in human cancer pathogenesis.Oncogene,2007,26:6469-6487.
46.Suzuki T,Takano Y,Kakita A,et al.An immunohistochemical and molecular biological study of c-erbB-2 amplification and prognostic relevance in gallbladder cancer.Pathol Res Pract,1993,189:283-292.
47.Chow NH,Huang SM,Chan SH,et al.Significance of c-erbB-2 expression in normal and neoplastic epithelium of biliary tract.Anticancer Res,1995,15:1055-1059.
48.Kamel D,Paakk(o|¨) P,Nuorva K,et al.p53 and c-erbB-2 protein expression in adenocarcinomas and epithelial dysplasias of the gall bladder.J Pathol,1993,170:63-72.
49.Matsuyama S,Kitajima Y,Sumi K,et al.Gallbladder cancers rarely overexpress HER-2/neu,demonstrated by Hercep test.Oncol Rep,2004,11:815-819.
50.Nakazawa K,Dobashi Y,Suzuki S,et al.Amplification and overexpression of c-erbB-2,epidermal growth factor receptor,and c-met in biliary tract cancers.J Pathol,2005,206:356-365.
51.王连刚,张惠中.癌基因c-erbB-2在胆囊癌中的异常表达及意义。细胞与分子免疫学杂志,1998,14:105-106.
52.Boudny V,Murakami Y,Nakano S,et al.Expression of activated c-erbB-2 oncogene induces sensitivity to cisplatin in human gallbladder adenocarcinoma cells.Anticancer Res,1999,19:5203-5206.
53. Guvakova MA. Insulin-like growth factors control cell migration in health and disease. Int J Biochem Cell Biol, 2007, 39: 890-909.
54. Leivonen SK, Kahari VM. Transforming growth factor-beta signaling in cancer invasion and metastasis. Int J Cancer, 2007, 121: 2119-2124.
55. Fomchenko EI, Holland EC. Platelet-derived growth factor-mediated gliomagenesis and brain tumor recruitment. Neurosurg Clin N Am, 2007, 18: 39-58.
56. Matsumoto K, Nakamura T. Hepatocyte growth factor and the Met system as a mediator of tumor-stromal interactions. Int J Cancer, 2006, 119: 477-483.
57. Bianco R, Gelardi T, Damiano V, et al. Rational bases for the development of EGFR inhibitors for cancer treatment. Int J Biochem Cell Biol, 2007, 39: 1416-1431.
58. Lee CS, Pirdas A. Epidermal growth factor receptor immunoreactivity in gallbladder and extrahepatic biliary tract tumours. Pathol Res Pract, 1995, 191: 1087-1091.
59. Lee CS. Transforming growth factor alpha immunoreactivity in human gallbladder and extrahepatic biliary tract tumours. Eur J Surg Oncol, 1998, 24: 38-42.
60. Yamamoto S, Kitadai Y, Tsuchida A, et al. Expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase in human gallbladder lesions. Eur J Cancer, 2000, 36: 257-263.
61. Kornprat P, Rehak P, Ruschoff J, et al. Expression of IGF-I, IGF-II, and IGF-IR in gallbladder carcinoma. A systematic analysis including primary and corresponding metastatic tumours. J Clin Pathol, 2006, 59: 202-206.
62. Kaneko K, Ando H, Ito T, et al. Increased cell proliferation and transforming growth factor-alpha (TGF alpha) in the gall-bladder epithelium of patients with pancreaticobiliary maljunction. Pathol Int, 1996, 46: 253-260.
63. Shimura H, Date K, Matsumoto K, et al. Induction of invasive growth in a gallbladder cancer cell line by hepatocyte growth factor in vitro. Jpn J Cancer Res,1995,86:662-669.
64. Li H, Shimura H, Aoki Y, et al. Hepatocyte growth factor stimulates the invasion of gallbladder carcinoma cell lines in vitro. Clin Exp Metastasis, 1998, 16: 74-82.
65. Date K, Matsumoto K, Kuba K, et al. Inhibition of tumor growth and invasion by a four-kringle antagonist (HGF/NK4) for hepatocyte growth factor. Oncogene, 1998,17: 3045-3054.
66.Musgrove EA.Cyclins:roles in mitogenic signaling and oncogenic transformation.Growth Factors,2006,24:13-19.
67.Shapiro GI.Cyclin-dependent kinase pathways as targets for cancer treatment.J Clin Oncol,2006,24:1770-1783.
68.Tashiro E,Tsuchiya A,Imoto M.Functions of cyclin D1 as an oncogene and regulation of cyclin D1 expression.Cancer Sci,2007,98:629-635.
69.Yasmeen A,Berdel WE,Serve H,et al.E-and A-type cyclins as markers for cancer diagnosis and prognosis.Expert Rev Mol Diagn,2003,3:617-633.
70.Berglund P,Landberg G.Cyclin e overexpression reduces infiltrative growth in breast cancer:yet another link between proliferation control and tumor invasion.Cell Cycle,2006,5:606-609.
71.Itoi T,Shinohara Y,Takeda K,et al.Nuclear cyclin D1 overexpression is a critical event associated with cell proliferation and invasive growth in gallbladder carcinogenesis.J Gastroenterol,2000,35:142-149.
72.Hui AM,Li X,Shi YZ,et al.Cyclin D1 overexpression is a critical event in gallbladder carcinogenesis and independently predicts decreased survival for patients with gallbladder carcinoma.Clin Cancer Res,2000,6:4272-4277.
73.Eguchi N,Fujii K,Tsuchida A,et al.Cyclin E overexpression in human gallbladder carcinomas.Oncol Rep,1999,6:93-96.
74.屠金夫,蒋飞照,陈必成.原发性胆囊癌细胞增殖与细胞周期素E表达的关系。中华实验外科杂志,2000,17:20-21.
75.牛坚,陈澍周,钱海鑫.Cyclin E、P27在原发性胆囊癌中表达及临床意义。肝胆胰外科杂志,2004,16:90-92.
76.Bourdon JC.p53 and its isoforms in cancer.Br J Cancer,2007,97:277-282.
77.Buschmann T,Potapova O,Bar-Shira A,et al.Jun NH2-terminal kinase phosphorylation of p53 on Thr-81 is important for p53 stabilization and transcriptional activities in response to stress.Mol Cell Biol,2001,21:2743-2754.
78.Harris SL,Levine AJ.The p53 pathway:Positive and negative feedback loops.Oncogene,2005,24:2899-2908.
79.Efeyan A,Serrano M.p53:guardian of the genome and policeman of the oncogenes.Cell Cycle,2007,6:1006-1010.
80. Palmero I, Pantoja C, Serrano M. p19ARF links the tumour suppressor p53 to Ras. Nature, 1998, 395: 125-126.
81. Wee A, Teh M, Raju GC. Clinical importance of p53 protein in gall bladder carcinoma and its precursor lesions. J Clin Pathol, 1994, 47: 453-456.
82. Hanada K, Itoh M, Fujii K, et al. TP53 mutations in stage I gallbladder carcinoma with special attention to growth patterns. Eur J Cancer, 1997, 33: 1136-1140.
83. Jonas S, Springmeier G, Tauber R, et al. p53 hot-spot mutational analysis in advanced Western gallbladder carcinoma. World J Surg, 1997, 21: 768-772.
84. Chaube A, Tewari M, Garbyal RS, et al. Preliminary study of p53 and c-erbB-2 expression in gallbladder cancer in Indian patients. BMC Cancer, 2006, 6: 126.
85. Chang HJ, Kim SW, Kim YT, et al. Loss of heterozygosity in dysplasia and carcinoma of the gallbladder. Mod Pathol, 1999, 12: 763-769.
86. Quan ZW, Wu K, Wang J, et al. Association of p53, p16, and vascular endothelial growth factor protein expressions with the prognosis and metastasis of gallbladder cancer. J Am Coll Surg, 2001, 193: 380-383.
87. Chang HJ, Yoo BC, Kim SW, et al. Significance of PML and p53 protein as molecular prognostic markers of gallbladder carcinomas. Pathol Oncol Res, 2007, 13:326-335.
88. Kamb A, Gruis NA, Weaver-Feldhaus J, et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science, 1994, 264: 436-440.
89. Canepa ET, Scassa ME, Ceruti JM, et al. INK4 proteins, a family of mammalian CDK inhibitors with novel biological functions. IUBMB Life, 2007, 59: 419-426.
90. Ruas M, Peters G The pl6INK4a/CDKN2A tumor suppressor and its relatives.Biochim Biophys Acta, 1998, 1378: F115-F177.
91. Esteller M, Corn PG, Baylin SB, et al. A gene hypermethylation profile of human cancer. Cancer Res, 2001, 61: 3225-3229.
92. Aggerholm A, Holm MS, Guldberg P, et al. Promoter hypermethylation of p15INK4B, HIC1, CDH1, and ER is frequent in myelodysplastic syndrome and predicts poor prognosis in early-stage patients. Eur J Haematol, 2006, 76: 23-32.
93. Sanchez-Aguilera A, Delgado J, Camacho FI, et al. Silencing of the pl8INK4c gene by promoter hypermethylation in Reed-Sternberg cells in Hodgkin lymphomas. Blood, 2004, 103: 2351-2357.
94. Ortega S, Malumbres M, Barbacid M. Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim Biophys Acta, 2002, 1602: 73-87.
95. EL-Deiry WS, Tokino T, Velculescu VE, et al. WAF1, a potential mediator of p53 tumor suppression. Cell, 1993, 75: 817-825.
96. Rowland BD, Peeper DS. KLF4, p21 and context-dependent opposing forces in cancer. Nat Rev Cancer, 2006, 6: 11-23.
97. Polyak K, Lee MH, Erdjument-Bromage H, et al. Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell, 1994, 78: 59-66.
98. Slingerland J, Pagano M. Regulation of the cdk inhibitor p27Kip1 and its deregulation in cancer. J Cell Physiol, 2000, 183: 10-17.
99. Matsuda Y, Ichida T, Genda T, et al. Loss of p16 contributes to p27 sequestration by cyclin D (1)-cyclin-dependent kinase 4 complexes and poor prognosis in hepatocellular carcinoma. Clin Cancer Res, 2003, 9: 3389-3396.
100.Han J, Tsukada Y, Hara E, et al. Hepatocyte growth factor induces redistribution of p21(CIP1) and p27(KIP1) through ERK-dependent p16(INK4a) up-regulation,leading to cell cycle arrest at Gl in HepG2 hepatoma cells. J Biol Chem, 2005, 280:31548-31556.
101.Kim YT, Kim J, Jang YH, et al. Genetic alterations in gallbladder adenoma, dysplasia and carcinoma. Cancer Lett, 2001, 169: 59-68.
102.Parwani AV, Geradts J, Caspers E, et al. Immunohistochemical and genetic analysis of non-small cell and small cell gallbladder carcinoma and their precursor lesions.Mod Pathol, 2003, 16: 299-308.
103.Ueki T, Hsing AW, Gao YT, et al. Alterations of p16 and prognosis in biliary tract cancers from a population-based study in China. Clin Cancer Res, 2004, 10:1717-1725.
104.Cobrinik D. Pocket proteins and cell cycle control. Oncogene, 2005, 24: 2796-2809.
105.Dimova DK, Dyson NJ. The E2F transcriptional network: Old acquaintances with new faces. Oncogene, 2005, 24: 2810-2826.
106.Mittnacht S. Control of pRB phosphorylation. Curr Opin Genet Dev, 1998, 8: 21-27.
107.Knudsen KE, Diehl JA, Haiman CA, et al. Cyclin D1: Polymorphism, aberrant splicing and cancer risk. Oncogene, 2006, 25: 1620-1628.
108.Xuan YH, Choi YL, Shin YK, et al. An immunohistochemical study of the expression of cell-cycle-regulated proteins p53, cyclin D1, RB, p27, Ki67 and MSH2 in gallbladder carcinoma and its precursor lesions. Histol Histopathol, 2005, 20:59-66.
109.Ma HB, Hu HT, Di ZL, et al. Association of cyclin D1, p16 and retinoblastoma protein expressions with prognosis and metastasis of gallbladder carcinoma. World J Gastroenterol, 2005, 11: 744-747.
110.Shi YZ, Hui AM, Li X, et al. Overexpression of retinoblastoma protein predicts decreased survival and correlates with loss of p16INK4 protein in gallbladder carcinomas. Clin Cancer Res, 2000, 6: 4096-4100.
111.Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science, 1997, 275: 1943-1947.
112.Weng L, Brown J, Eng C. PTEN induces apoptosis and cell cycle arrest through phosphoinositol-3-kinase/Akt-dependent and -independent pathways. Hum Mol Genet, 2001, 10:237-242.
113.Tumura M, Gu J, Takino, et al. Tumor suppressor PTEN inhibition of cell invasion,migration, and growth: differential involvement of focal adhesion kinase and p130~(cas).Cancer Res, 1999, 59: 442-449.
114.Weng LP, SmithWM, Brown TL, et al. PTEN inhibits insulin-stimulated MEK/MAPK activation and cell grovth by blocking IRS21 phosphorylation and IRS21/Grb22/Sos complex formation in a breast model. Hum Mol Genet, 2001, 10:605-616.
115.Groden J, Thliveris A, Samowitz W, et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell, 1991, 66: 589-600.
116.Homma MK, Li D, Krebs EG, et al. Association and regulation of casein kinase 2 activity by adenomatous polyposis coli protein. Proc Natl Acad Sci U S A, 2002, 99:5959-5964.
117.Fearon ER, Cho KR, Nigro JM, et al. Identification of a chromosome 18q gene that is altered in colorectal cancers. Science, 1990, 247: 49-56.
118.Keino-Masu K,Masu M,Hinck L,et al.Deleted in Colorectal Cancer(DCC)encodes a netrin receptor.Cell,1996,75:175-185.
119.Hahn SA,Schutte M,Hoque AT,et al.DPC4,a candidate tumor suppressor gene at human chromosome 18q21.1.Science,1996,271:350-353.
120.Riggins GJ,Kinzler KW,Vogelstein B,et al.Frequency of Smad gene mutations in human cancers.Cancer Res,1997,57:2578-2580.
121.Zawel L,Dai JL,Buckhaults P,et al.Human Smad3 and Smad4 are sequence-specific transcription activators.Mol Cell,1998,1:611-617.
122.李海,吴晓阳,颜鸣.抑癌基因PTEN蛋白在胆囊癌中的表达及临床病理意义。现代肿瘤医学,2006,14:972-974.
123.黄英,郑长黎.原发性胆囊癌中PTEN和P53基因表达的研究。中国癌症杂志,2006,16:547-550.
124.Yoshida T,Sugai T,Habano W,et al.Microsatellite instability in gallbladder carcinoma:two independent genetic pathways of gallbladder carcinogenesis.J Gastroenterot,2000,35:768-774.
125.Takahashi T,Shivapurkar N,Riquelme E,et al.Aberrant promoter hypermethylation of multiple genes in gallbladder carcinoma and chronic cholecystitis.Clin Cancer Res,2004,10:6126-6133.
126.Roa JC,Anabal6n L,Roa I,et al.Promoter methylation profile in gallbladder cancer.J Gastroenterol,2006,41:269-275.
127.Wistuba II,Sugio K,Hung J,et al.Allele-specific mutations involved in the pathogenesis of endemic gallbladder carcinoma in Chile.Cancer Res,1995,55:2511-2515.
128.Chuang SC,Lee KT,Tsai KB,et al.Immunohistochemical study of DPC4 and p53proteins in gallbladder and bile duct cancers.World J Surg,2004,28:995-1000.
129.Cory S,Adams JM.The Bcl2 family:regulators of the cellular life-or-death switch.Nat Rev Cancer,2002,2:647-656.
130.Bakhshi A,Wright JJ,Graninger W,et al.Mechanism of the t(14;18) chromosomal translocation:structural analysis of both derivative 14 and 18 reciprocal partners.Proc Natl Acad Sci USA,1987,84:2396-2400.
131.McDonnell TJ,Korsmeyer SJ.Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14;18). Nature, 1991, 349:254-256.
132.Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature, 1988, 335: 440-442.
133.Bissonnette RP, Echeverri F, Mahboubi A, et al. Apoptotic cell death induced by c-myc is inhibited by bcl-2. Nature, 1992, 359: 552-554.
134.Vander Heiden MG, Li XX, Gottleib E, et al. Bcl-xL promotes the open configuration of the voltage-dependent anion channel and metabolite passage through the outer mitochondrial membrane. J Biol Chem, 2001, 276: 19414-19419.
135.He L, Perkins GA, Poblenz AT, et al. Bcl-xL overexpression blocks bax-mediated mitochondrial contact site formation and apoptosis in rod photoreceptors of lead-exposed mice. Proc Natl Acad Sci U S A, 2003, 100: 1022-1027.
136.Wei MC, Zong WX, Cheng EH, et al. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science, 2001, 292: 727-730.
137.Sasatomi E, Tokunaga O, Miyazaki K. Spontaneous apoptosis in gallbladder carcinoma. Relationships with clinicopathologic factors, expression of E-cadherin,bcl-2 protooncogene, and p53 oncosuppressor gene. Cancer, 1996, 78: 2101-2110.
138.Mikami T, Yanagisawa N, Baba H, et al. Association of Bcl-2 protein expression with gallbladder carcinoma differentiation and progression and its relation to apoptosis.Cancer, 1999,85:318-325.
139.Ariyama H, Qin B, Baba E, et al. Gefitinib, a selective EGFR tyrosine kinase inhibitor, induces apoptosis through activation of Bax in human gallbladder adenocarcinoma cells. J Cell Biochem, 2006, 97: 724-734.
140.Ai Z, Lu W, Qin X. Arsenic trioxide induces gallbladder carcinoma cell apoptosis via downregulation of Bcl-2. Biochem Biophys Res Commun, 2006, 348: 1075-1081.
141.Falschlehner C, Emmerich CH, Gerlach B, et al. TRAIL signalling: decisions between life and death. Int J Biochem Cell Biol, 2007, 39: 1462-1475.
142.Sprick MR, Walczak H. The interplay between the Bcl-2 family and death receptor-mediated apoptosis. Biochim Biophys Acta, 2004, 1644: 125-132.
143.Xu LN, Zou SQ, Wang JM. Action and mechanism of Fas and Fas ligand in immune escape of gallbladder carcinoma. World J Gastroenterol, 2005, 11: 3719-3723.
144.Duffy MJ,O'Donovan N,Brennan DJ,et al.Survivin:a promising tumor biomarker.Cancer Lett,2007,249:49-60.
145.Grossman D,Kim PJ,Blanc-Brude O,et al.Transgenic expression of survivin in keratinocytes counteracts UVB-induced apoptosis and cooperates with loss of p53.J Clin Invest,2001,108:991-999.
146.Pennati M,Colella G,Folini L,et al.Ribozyme-mediated attenuation of surviving expression sensitizes human melanoma cells to cis-platininduced apoptosis.J Clin Invest,2002,109:285-286.
147.Shin BC,Sung BJ,Kim H,et al.An antiapoptotic protein human survivin is a direct inhibitor of caspase-3 and -7.Biochemistry,2001,40:1117-1123.
148.Banks DP,Plescia J,Altieri DC.Survivin does not inhibit caspase-3 activity.Blood,2000,96:4002.
149.Marusawa H,Matsuzawa S,Welsh K,et al.HBXIP functions as a cofactor of surviving in apoptosis suppression.EMBO J,2003,22:2729-2740.
150.Du C,Fang M,Li Y,et al.Smac a mitochondrial protein that promotes cytochrome C-dependent caspase activation by eliminating IAP inhibition.Cell,2000,102:33-42.
151.牛坚,陆艺,钱海鑫.Survivin在原发性胆囊癌中的表达及其临床意义。苏州大学学报·医学版,2006,26:277-278,293.
152.万云乐,丁伟,郑树森,等.原发性胆囊癌Survivin和Ki-67的表达及意义。中华实验外科杂志,2006,23:919-921.
153.沈汉斌,郑启昌.胆囊癌GBC-SD细胞经顺铂处理后的survivin表达及意义。中国普通外科杂志,2007,16:129-132.
154.冯立民,姜希宏,乌新林,等.survivin反义寡核苷酸诱导胆囊癌细胞凋亡的研究。中国普外基础与临床杂志,2006,13:298-301.
155.沈汉斌,郑启昌,王国斌,等.Survivin shRNA表达质粒的构建及其抑制survivin 表达的初步研究。中国普通外科杂志,2006,15:927-931.
156.Liu J,Jiang G.CD44 and hematologic malignancies.Cell Mol Immunol,2006,3:359-365.
157.G(o|¨)tte M,Yip GW.Heparanase,hyaluronan,and CD44 in cancers:a breast carcinoma perspective.Cancer Res,2006,66:10233-10237.
158.Watanabe O,Kinoshita J,Shimizu T,et al.Expression of a CD44 variant and VEGF-C and the implications for lymphatic metastasis and long-term prognosis of human breast cancer.J Exp Clin Cancer Res,2005,24:75-82.
159.Lopez JI,Camenisch TD,Stevens MV,et al.CD44 attenuates metastatic invasion during breast cancer progression.Cancer Res,2005,65:6755-6763.
160.Bourguignon LY,Singleton PA,Zhu H,et al.Hyaluronan-mediated CD44 interaction with RhoGEF and Rho kinase promotes Grb2-associated binder-1 phosphorylation and phosphatidylinositol 3-kinase signaling leading to cytokine(macrophage-colony stimulating factor) production and breast tumor progression.J Biol Chem,2003,278:29420-29434.
161.Yanagisawa N,Mikami T,Mitomi H,et al.CD44 variant overexpression in gallbladder carcinoma associated with tumor dedifferentiation.Cancer,2001,91:408-416.
162.韩玥,石景森,朱爱军,等.胆囊癌中CD44v6和基质金属蛋白酶-2的表达及其临床意义。中国普通外科杂志,2002,11:98-101.
163.谷化平,尚培中,刘艳茹.原发性胆囊癌CD44v6和bcl-2的表达及其与临床病理的关系。中国普外基础与临床杂志,2003,10:46-48.
164.Steeg PS,Bevilacqua G,Kopper L,et al.Evidence for a novel gene associated with low tumor metastatic potential.J Natl Cancer Inst,1988,80:200-204.
165.Sadek CM,Jimenez A,Damdimopoulos AE,et al.Characterization of human thioredoxin-like 2.A novel microtubule-binding thioredoxin expressed predominantly in the cilia of lung airway epithelium and spermatid manchette and axoneme.J Biol Chem,2003,278:13133-13142.
166.Howlett AR,Peterson OW,Steeg PS,et al.A novel function for the nm23-H1 gene:overexpression in human breast carcinoma cells leads to the formation of basement membrane and growth arrest.J Natl Cancer Inst,1994,86:1838-1844.
167.Fan Z,Beresford PJ,Oh DY,et al.Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-mediated apoptosis,and the nucleosome assembly protein SET is its inhibitor.Cell,2003,112:659-672.
168.Ma D,McCorkle JR,Kaetzel DM.The metastasis suppressor NM23-H1 possesses 3'-5' exonuclease activity.J Biol Chem,2004,279:18073-18084.
169.Ouatas T,Salerno M,Palmieri D,et al.Basic and translational advances in cancer metastasis:Nm23.J Bioenerg Biomembr,2003,35:73-79.
170.Fujii K,Yasui W,Shimamoto F,et al.Immunohistochemical analysis of nm23 gene product in human gallbladder carcinomas.Virchows Arch,1995,426:355-359.
171.Lee CS,Pirdas-Zivcic A.nm23-H1 protein immunoreactivity in cancers of the gallbladder,extrahepatic bile ducts and ampulla of Vater.Pathology,1994,26:448-452.
172.韩庆,高寰,康亚安,等.胆囊癌组织中NDPK/nm23的表达及意义。中华普通外科杂志,1997,12:280-282.
173.史朝晖,孙现军,常新忠,等.胆囊癌组织中nm232H1和p16蛋白表达的意义。肿瘤防治杂志,2002,9:597-598.
174.Verma RP,Hansch C.Matrix metalloproteinases(MMPs):chemical-biological functions and(Q)SARs.Bioorg Med Chem,2007,15:2223-2268.
175.Aranapakam V,Grosu GT,Davis JM,et al.Synthesis and structure-activity relationship of alpha-sulfonylhydroxamic acids as novel,orally active matrix metalloproteinase inhibitors for the treatment of osteoarthritis.J Med Chem,2003,46:2361-2375.
176.Venkatesan AM,Davis JM,Grosu GT,et al.Synthesis and structure-activity relationships of 4-alkynyloxy phenyl sulfanyl,sulfinyl,and sulfonyl alkyl hydroxamates as tumor necrosis factor-alpha converting enzyme and matrix metalloproteinase inhibitors.J Med Chem,2004,47:6255-6269.
177.Overall CM,Kleifeld O.Tumour microenvironment-opinion:validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy.Nat Rev Cancer,2006,6:227-239.
178.Bergers G,Brekken R,McMahon G,et al.Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis.Nat Cell Biol,2000,2:737-744.
179.Hofmann UB,Eggert AA,Blass K,et al.Expression of matrix metalloproteinases in the microenvironment of spontaneous and experimental melanoma metastases reflects the requirements for tumor formation.Cancer Res,2003,63:8221-8225.
180.Kido A,Tsutsumi M,Iki K,et al.Overexpression of matrix metalloproteinase (MMP)-9 correlates with metastatic potency of spontaneous and 4-hydroxyaminoquinoline 1-oxide(4-HAQO)-induced transplantable osteosarcomas in rats.Cancer Lett,1999,137:209-216.
181.Agarwal D,Goodison S,Nicholson B,et al.Expression of matrix metalloproteinase 8(MMP-8) and tyrosinaserelated protein-1(TYRP-1) correlates with the absence of metastasis in an isogenic human breast cancer model.Differentiation,2003,71:114-125.
182.McCawley LJ,Crawford HC,King LE,Jr.,et al.A protective role for matrix metalloproteinase-3 in squamous cell carcinoma.Cancer Res,2004,64:6965-6972.
183.Karadag N,Kirimlioglu H,Isik B,et al.Expression of matrix metalloproteinases in gallbladder carcinoma and their significance in carcinogenesis.Appl Immunohistochem Mol Morphol,2008,in press.
184.范跃祖,张景涛.基质金属蛋白酶-2及其组织抑制因子在原发性胆囊癌的表达及意义。中国肿瘤临床,2004,31:675-678.
185.王新保,彭淑牖,郭剑民,等.MMP-7、TIMP-1在胆囊癌组织中的表达。肿瘤防治杂志,2005,14:199-201.
186.牛坚,陈澍周,钱海鑫.TGF-β1和MMP-2在胆囊癌中表达及临床意义。肿瘤防治杂志,2005,12:686-689.
187.Crippa MP.Urokinase-type plasminogen activator.Int J Biochem Cell Biol,2007,39:690-694.
188.Ibanez-Tallon I,Ferrai C,Longobardi E,et al.Binding of Spl to the proximal promoter links constitutive expression of the human uPA gene and invasive potential of PC3 cells.Blood,2002,100:3325-3332.
189.Jankun J,Merrick HW,Goldblatt PJ.Expression and localization of elements of the plasminogen activation system in benign breast disease and breast cancers.J Cell Biochem,1993,53:135-144.
190.Nakajima M,Chop AM.Tumor invasion and extracellular matrix degradative enzymes:regulation of activity by organ factors.Semin Cancer Biol,1991,2:115-127.
191.Alfano D,Iaccarino I,Stoppelli MP.Urokinase signaling through its receptor protects against anoikis by increasing BCL-xL expression levels.J Biol Chem,2006,281:17758-17767.
192.焦兴元,吕明德,黄洁夫,等.胆囊癌患者凝血及纤溶分子标志物的变化研究。肝胆外科杂志,2003,11:349-351.
193.Seo E,Abei M,Wakayama M,et al.Effective gene therapy of biliary tract cancers by a conditionally replicative adenovirus expressing uracil phosphoribosyltransferase:significance of timing of 5-fluorouracil administration.Cancer Res,2005,65:546-552.
194.Tekant Y,Davydova J,Ramirez PJ,et al.Oncolytic adenoviral therapy in gallbladder carcinoma.Surgery,2005,137:527-535.
195.Wu Q,Kiguchi K,Kawamoto T,et al.Therapeutic effect of rapamycin on gallbladder cancer in a transgenic mouse model.Cancer Res,2007,67:3794-3800.
196.靳斌,王伟,姜希宏,等.核酶切割技术对胆囊癌细胞端粒酶活性抑制作用的研究。中国普通外科杂志,2006,15:198-201.
197.丁昂,童赛雄,冯平,等.吲哚美辛和hTERT-siRNA对胆囊癌细胞的作用。复旦学报·医学版,2006,33:614-618.
198.刘刚,仟宏,孙学军,等.脐血源性CIK细胞的体外增殖及其对人胆囊癌细胞株GBC-SD杀伤活性的实验研究。中华肝胆外科杂志,2007,13:540-543.
199.乌新林,董培德,欧阳晓晖,等.野生型p53基因抑制胆囊癌细胞裸鼠体内生长的实验研究。内蒙古医学院学报,2007,29:233-238.
200.逄锦忠,童赛雄,锁涛,等.单纯疱疹病毒胸苷激酶/丙氧鸟苷自杀基因系统对胆囊癌细胞的体外作用。中华实验外科杂志,2004,21:945-947.
201.常新忠,王古民,张毅,等.双自杀基因体系对胆囊癌细胞体内外杀伤作用的研究。中华普通外科杂志,2004,19:631-633.
2. Lazcano-Ponce EC, Miquel JF, Munoz N, et al. Epidemiology and molecular pathology of gallbladder cancer. CA Cancer J Clin, 2001, 51: 349-364.
3. Pandey M. Risk factors for gallbladder cancer: A reappraisal. Eur J Cancer Prev,2003,12: 15-24.
4. Nandakumar A, Gupta PC, Gangadharan P, et al. Geographic pathology revisited: Development of an atlas of cancer in India. Int J Cancer, 2005, 116: 740-754.
5. Misra S, Chaturvedi A, Misra NC, et al. Carcinoma of the gallbladder. Lancet Oncol,2003,4:167-176.
6. Lowen fels AB, lindstrom CG, Conway MJ. Gall stones and risk of gall bladder cancer. JNCI, 1985, 75: 77-80.
7. Arundhati Rai, Mohapatra SC, Shukla HS. A review of association of dietary factor in gall bladder cancer. IJC, 2004, 75: 368-370.
8. Chao TC, Jan YY, Chen MF. Primary carcinoma of the gall bladder associated with anomalous pancreatio biliary ductal junction. J Clin Gastoenterol, 1995, 21: 306-309.
9. Kumar S, Kumar S, Kumar S. Infection as a risk factor for gallbladder cancer. J Surg Oncol, 2006, 93: 633-639.
10. Carriaga MT, Henson DE. Liver, gallbladder, extrahepatic bile ducts, and pancreas.Cancer, 1995,75: 171-190.
11. Cubertafond P, Gainant A, Cucchiaro G Surgical treatment of 724 carcinomas of the gallbladder. Results of the French Surgical Association Survey. Ann Surg, 1994, 219:275-280.
12. Wilkinson DS. Carcinoma of the gall-bladder: an experience and review of the literature. Aust NZ J Surg, 1995, 65: 724-727.
13. Wakai T, Shirai Y, Yokoyama N, et al. Early gallbladder carcinoma does not warrant radical resection. Br J Surg, 2001, 88: 675-678.
14. Ito H, Matros E, Brooks DC, et al. Treatment outcomes associated with surgery for gallbladder cancer:a 20-year experience.J Gastrointest Surg,2004,8:183-190.
15.Hsing AW,Gao YT,Devesa SS,et al.Rising incidence of biliary tract cancers in Shanghai,China.Int J Cancer,1998,75:368-370.
16.张微,项永兵,刘振伟,等.1973-1999年上海市区老年人恶性肿瘤发病趋势分析。中华老年医学杂志,2005,24:701-704.
17.马新源,汪祥辉,雷通海,等.嘉善县恶性肿瘤发病率及动态研究。中国肿瘤,2001,10:378-380.
18.石景森,杨毅军,赵凤林,等.原发性胆囊癌44年诊治的临床回顾。外科理论与实践,2001,6:137-141.
19.Zou S,Zhang L,Zen G,et al.Clinical epidemiologic characteristics of 430 cases of gallbladder cancer.Chin Med J,1998,111:391-393.
20.Hsing AW,Gao YT,Han TQ,et al.Gallstones and the risk of biliary tract cancer:a population-based study in China.Br J Cancer,2007,97:1577-1582.
21.Malats N,Porta M,Pinol JL,et al.Ki-ras mutations as a prognostic factor in extrahepatic bile system cancer.J Clin Oncol,1995,13:1679-1686.
22.Hanada K,Tsuchida A,Iwao T,et al.Gene mutations of K-ras in gallbladder mucosa and gallbladder carcinoma with an anomalous junction of the pancreaticobiliary duct.Am J Gastroenterol,1999,94:1638-1642.
23.Suzuki T,Takano Y,Kakita A,et al.An immunohistochemical and molecular biological study of c-erbB-2 amplification and prognostic relevance in gallbladder cancer.Pathol Res Pract,1993,189:283-292.
24.Nakazawa K,Dobashi Y,Suzuki S,et al.Amplification and overexpression of c-erbB-2,epidermal growth factor receptor,and c-met in biliary tract cancers.J Pathol,2005,206:356-365.
25.Itoi T,Shinohara Y,Takeda K,et al.Nuclear cyclin D1 overexpression is a critical event associated with cell proliferation and invasive growth in gallbladder carcinogenesis.J Gastroenterol,2000,35:142-149.
26.Hui AM,Li X,Shi YZ,et al.Cyclin D1 overexpression is a critical event in gallbladder carcinogenesis and independently predicts decreased survival for patients with gallbladder carcinoma.Clin Cancer Res,2000,6:4272-4277.
27.Hanada K,Itoh M,Fujii K,et al.TP53 mutations in stage Ⅰ gallbladder carcinoma with special attention to growth patterns.Eur J Cancer,1997,33:1136-1140.
28.Chang HJ,Yoo BC,Kim SW,et al.Significance of PML and p53 protein as molecular prognostic markers of gallbladder carcinomas.Pathol Oncol Res,2007,13:326-335.
29.Parwani AV,Geradts J,Caspers E,et al.Immunohistochemical and genetic analysis of non-small cell and small cell gallbladder carcinoma and their precursor lesions.Mod Pathol,2003,16:299-308.
30.Ueki T,Hsing AW,Gao YT,et al.Alterations of p16 and prognosis in biliary tract cancers from a population-based study in China.Clin Cancer Res,2004,10:1717-1725.
31.Shi YZ,Hui AM,Li X,et al.Overexpression of retinoblastoma protein predicts decreased survival and correlates with loss of p16INK4 protein in gallbladder carcinomas.Clin Cancer Res,2000,6:4096-4100.
32.黄英,郑长黎.原发性胆囊癌中PTEN和P53基因表达的研究。中国癌症杂志,2006,16:547-550.
33.Takahashi T,Shivapurkar N,Riquelme E,et al.Aberrant promoter hypermethylation of multiple genes in gallbladder carcinoma and chronic cholecystitis.Clin Cancer Res,2004,10:6126-6133.
34.Roa JC,Anabal6n L,Roa I,et al.Promoter methylation profile in gallbladder cancer.J Gastroenterol,2006,41:269-275.
35.Mikami T,Yanagisawa N,Baba H,et al.Association of Bcl-2 protein expression with gallbladder carcinoma differentiation and progression and its relation to apoptosis.Cancer,1999,85:318-325.
36.Yanagisawa N,Mikami T,Mitomi H,et al.CD44 variant overexpression in gallbladder carcinoma associated with tumor dedifferentiation.Cancer,2001,91:408-416.
37.刘军建,张杰,张宁,等.用荧光差异显示法分离新的肝细胞癌相关基因。北京医科大学学报,2000,32:411-414.
38.Liu J,Zhou RL,Zhang N,et al.Biological function of a novel gene overexprcsscd in human hepatocellular carcinoma.Chin Med J,2000,113:881-885.
39.Shao GZ,Zhou RL,Zhang QY,et al.Molecular cloning and characterization of LAPTM4B,a novel gene upregulated in hepatocellular carcinoma.Oncogene,2003,22:5060-5069.
40.邵根泽.人肝细胞癌相关基因LAPTM4B的克隆及其功能研究。北京大学医学部博士学位论文,2003.
41.邓丽娟,张青云,刘波,等.LAPTM4B基因多态性与肺癌易感性的关系。北京大学学报(医学版),2005,37:302-305.
42.Liu Y,Zhang QY,Qian N,et al.Relationship between LAPTM4B gene polymorphism and susceptibility of gastric cancer.Ann Oncol,2007,18:311-316.
43.Cheng XJ,Xu W,Zhang QY,et al.Relationship between LAPTM4B gene polymorphism and susceptibility of colorectal and esophageal cancers.Ann Oncol,2008,19:527-532.
44.刘歆荣,周柔丽,张青云,等.人肝癌相关新基因编码产物LAPTM4B的鉴定及其生物学特性。北京大学学报(医学版),2003,35:340-347.
45.Liu XR,Zhou RL,Zhang QY,et al.Structure analysis and expressions of a novel tetratransmembrane protein,lysosoma-associated protein transmembrane 4 beta associated with hepatocellular carcinoma.World J Gastroenterol,2004,10:1555-1559.
46.何静,邵根泽,周柔丽.肝癌中高表达的新基因LAPTM4B对细胞增殖及成瘤性的影响。北京大学学报(医学版),2003,35:348-352.
47.Peng C,Zhou RL,Shao GZ,et al.Expression of lysosome-associated protein transmembrane 4B-35 in cancer and its correlation with the differentiation status of hepatocellular carcinoma.World J Gastroenterol,2005,11:2704-2708.
48.Kasper G,Vogel A,Klaman I,et al.The human LAPTM4b transcript is upregulated in various types of solid tumours and seems to play a dual functional role during tumour progression.Cancer Lett,2005,224:93-103.
49.Morris DG,Musat M,Czirjak S,et al.Differential gene expression in pituitary adenomas by oligonucleotide array analysis.Eur J Endocrinol,2005,153:143-151.
50.Nevin JE,Moran TJ,Kay S,et al.Carcinoma of the gallbladder:staging,treatment,and prognosis.Cancer,1976,37:141-148.
51. Hogue DL, Kerby L, Ling V. A mammalian lysosomal membrane protein confers multidrug resistance upon expression in Saccharomyces cerevisiae. J Biol Chem,1999,274: 12877-12882.
52. Sanz-Altamira PM, Ferrante K, Jenkins RL, et al. A phase II trial of 5-fluorouracil,leucovorin, and carboplatin in patients with unresectable biliary tree carcinoma.Cancer, 1998,82:2321-2325.
53. Wakai T, Shirai Y, Yokoyama N, et al. Depth of subserosal invasion predicts long-term survival after resection in patients with T2 gallbladder carcinoma. Ann Surg Oncol, 2003, 10: 447-454.
54. Nakata T, Kobayashi A, Miwa S, et al. Impact of tumor spread to the cystic duct on the prognosis of patients with gallbladder carcinoma. World J Surg 2007, 31:155-161.
55. Wakabayashi H, Ishimura K, Hashimoto N, et al. Analysis of prognostic factors after surgery for stage III and IV gallbladder cancer. Eur J Surg Oncol, 2004, 30: 842-846.
56. Noshiro H, Chijiiwa K, Yamaguchi K, et al. Factors affecting surgical outcome for gallbladder carcinoma. Hepatogastroenterology, 2003, 50: 939-944.
57. Aramaki M, Matsumoto T, Shibata K, et al. Factors influencing recurrence after surgical treatment for T2 gallbladder carcinoma. Hepatogastroenterology, 2004, 51:1609-1611.
58. Kai M, Chijiiwa K, Ohuchida J, et al. A curative resection improves the postoperative survival rate even in patients with advanced gallbladder carcinoma. J Gastrointest Surg, 2007, 11: 1025-1032.
59. Sasaki E, Nagino M, Ebata T, et al. Immunohistochemically demonstrated lymph node micrometastasis and prognosis in patients with gallbladder carcinoma. Ann Surg, 2006, 244: 99-105.
60. Hui AM, Li X, Shi YZ, et al. p27(Kip1) expression in normal epithelia, precancerous lesions, and carcinomas of the gallbladder: association with cancer progression and prognosis. Hepatology, 2000, 31: 1068-1072.
61. Varga M, Obrist P, Schneeberger S, et al. Overexpression of epithelial cell adhesion molecule antigen in gallbladder carcinoma is an independent marker for poor survival. Clin Cancer Res, 2004, 10: 3131-3136.
62.Li SH,Li CF,Sung MT,et al.Skp2 is an independent prognosticator of gallbladder carcinoma among p27(Kip1)-interacting cell cycle regulators:an immunohistochemical study of 62 cases by tissue microarray.Mod Pathol,2007,20:497-507.
63.Jiang W,Kahn SM,Zhou P,et al.Overexpression of cyclin D1 in rat fibroblasts causes abnormalities in growth control,cell cycle progression and gene expression.Oncogene,1993,8:3447-3457.
64.Polyak K,Lee M,Erdjement-Bromage H,et al.Cloning of p27~(Kipl),a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals.Cell,1994,79:59-66.
65.Sutterluty H,Chatelain E,Marti A,et al.p45~(Skp2) promotes p27~(Kipl) degradation and induces S phase in quiescent cells.Nat Cell Biol,1999,1:207-214.
66.Koyama S,Yoshioka T,Mizushima A,et al.Establishment of a cell line(G-415)from a human gallbladder carcinoma.Jpn J Cancer Res,1980,71:574-575.
67.Knuth A,Gabbert H,Dippold W,et al.Biliary adenocarcinoma:characterisation of three new human tumor cell lines.J Hepatol,1985,1:579-596.
68.Nakano S,Tatsumoto T,Esaki T,et al.Characterization of a newly established human gallbladder carcinoma cell line.In Vitro Cell Dev Biol Anim,1994,30A:729-732.
69.Nishida T,Iwasaki H,Johzaki H,et al.A human gallbladder signet ring cell carcinoma cell line.Pathol Int,1997,47:368-376.
70.刘博,王古民,吴小鹏,等.人胆囊癌细胞系GBC-SD的建立。山东医科大学学报,2000,38:332-333.
71.刘博,王古民,吴小鹏,等.胆囊癌细胞系GBC-SD的牛物学行为研究。外科理论与实践,2001,6:146-148.
72.李东华,王古民,刘军,等.人胆囊癌细胞系GBC-SD的多药耐药机制。中华实验外科杂志,2003,20:995-997.
73.乌新林,王古民,马道新,等.人胆囊癌细胞系GBC-SD p53基因突变的研究。山东大学学报·医学版,2005,43:66-68.
74.乌新林,施琳,罗力,等.稳定表达外源野生型p53基因人胆囊癌细胞系的建 立和鉴定。内蒙古医学院学报,2005,27:189-192.
75.乌新林,王占民,杨凤辉,等.野生型p53基因对人胆囊癌细胞生长及致瘤性的抑制作用。中国肿瘤生物治疗杂志,2005,12:266-271.
76.刘颖斌,何小伟,王建伟,等.胆囊癌肝转移模型的建立和高转移细胞亚群的筛选。中华医学杂志,2006,86:2117-2121.
77.Chang XZ,Wang ZM,Yu JM,et al.Isolation of a human gallbladder cancer cell clone with high invasive phenotype in vitro and metastatic potential in orthotopic model and inhibition of its invasiveness by heparanase antisense oligodeoxynucleotides.Clin Exp Metastasis,2007,24:25-38.
78.冯立民,王建立,乌新林,等.单独及联合转染survivin和bcl-2反义寡核苷酸诱导胆囊癌细胞凋亡的研究。中国肿瘤生物治疗杂志,2004,11:248-251.
79.Ai Z,Lu W,Ton S,et al.Arsenic trioxide-mediated growth inhibition in gallbladder carcinoma cells via down-regulation of Cyclin D1 transcription mediated by Sp1transcription factor.Biochem Biophys Res Commun,2007,360:684-689.
80.范跃祖,傅锦业,赵泽明,等.去甲斑蝥素对人胆囊癌GBC-SD细胞系增殖及侵袭的影响。中华肿瘤杂志,2004,26:271-274.
81.Oster SK,Ho CS,Soucie EL,et al.The myc oncogene:Marvelously complex.Adv Cancer Res,2002,84:81-154.
82.Milde-Langosch K.The Fos family of transcription factors and their role in tumourigenesis.Eur J Cancer,2005,41:2449-2461.
83.van Dam H,Castellazzi M.Distinct roles of Jun:Fos and Jun:ATF dimers in oncogenesis.Oncogene,2001,20:2453-2464.
84.Jochum W,Passegue E,Wagner EF.AP-1 in mouse development and tumourigenesis.Oncogene,2001,20:2401-2412.
85.Shaulian E,Karin M.AP-1 in cell proliferation and survival.Oncogene,2001,20:2390-2400.
86.Shaulian E,Karin M.AP-1 as a regulator of cell life and death.Nat Cell Biol,2002,4:E131-E136.
87.Jiang W,Kahn SM,Zhou P,et al.Overexpression of cyclin D1 in rat fibroblasts causes abnormalities in growth control,cell cycle progression and gene expression. Oncogene,1993,8:3447-3457.
88.Ohtsubo M,Roberts JM.Cyclin-dependent regulation of G1 in mammalian fibroblasts.Science,1993,259:1908-1912.
89.孙丽,张青云.人肝癌相关新基因LAPTM4B研究进展。世界华人消化杂志,2006,14:1805-1809.
90.Sherr CJ.G1 phase progression:Cycling on cue.Cell,1994,79:551-555.
91.Malumbres M,Barbacid M.Mammalian cyclin-dependent kinases.Trends Biochem Sci,2005,30:630-641.
92.Cánepa ET,Scassa ME,Ceruti JM,et al.INK4 proteins,a family of mammalian CDK inhibitors with novel biological functions.IUBMB Life,2007,59:419-426.
93.Gartel AL,Shchors K.Mechanisms of c-myc-mediated transcriptional repression of growth arrest genes.Exp Cell Res,2003,283:17-21.
94.Mook OR,Frederiks WM,Van Noorden CJ.The role of gelatinases in colorectal cancer progression and metastasis.Biochim Biophys Acta,2004,1705:69-89.
95.Nakajima M,Chop AM.Tumor invasion and extracellular matrix degradative enzyme:regulation of activity by organ factors.Semin Cancer Biol,1991,2:115-127.
96.Shah V,Kumar S,Zirvi KA.Metastasis of human colon tumor cells in vivo:correlation with the overexpression of plasminogen activators and 72 kDa gelatinase.In Vivo,1994,8:321-326.
97.Hyuga S,Nishikawa Y,Sakata K,et al.Autocrine factor enhancing the secretion of M(r) 95,000 gelatinase(matrix metalloproteinase 9) in serum-free medium conditioned with murine metastatic colon carcinoma cells.Cancer Res,1994,54:3611-3616.
98.Jankun J,Merrick HW,Goldblatt PJ.Expression and localization of elements of the plasminogen activation system in benign breast disease and breast cancers.J Cell Biochem,1993,53:135-144.
99.Yan C,Boyd DD.Regulation of matrix metalloproteinase gene expression.J Cell Physiol,2007,211:19-26.
100.Qin H,Sun Y,Benveniste EN.The transcription factors Sp1,Sp3,and AP-2 are required for constitutive matrix metalloproteinase-2 gene expression in astroglioma cells. J Biol Chem, 1999, 274: 29130-29137.
101.Mazzieri R, Masiero L, Zanetta L, et al. Control of type IV collagenase activity by components of the urokinase-plasmin system: a regulatory mechanism with cell-bound reactants. EMBOJ, 1997, 16: 2319-2332.
102.Liu GY, Frank N, Bartsch H, et al. Induction of apoptosis by thiuramdisulfides, the reactive metabolites of dithiocarbamates, through coordinative modulation of NFkappaB, c-fos/c-jun, and p53 proteins. Mol Carcinog, 1998, 22: 235-246.
103.Takeuchi K, Motoda Y, Ito F. Role of transcription factor activator protein 1 (AP1) in epidermal growth factor-mediated protection against apoptosis induced by a DNA-damaging agent. FEBS J, 2006, 273: 3743-3755.
104.Hemann MT, Lowe SW. The p53-Bcl-2 connection. Cell Death Differ, 2006, 13:1256-1259.
105.Pelengaris S, Khan M. The many faces of c-MYC. Arch Biochem Biophys, 2003,416: 129-136.
106.Conzen SD, Gottlob K, Kandel ES, et al. Induction of cell cycle progression and acceleration of apoptosis are two separable functions of c-Myc: transrepression correlates with acceleration of apoptosis. Mol Cell Biol, 2000, 20: 6008-6018.
1.Kapoor VK.Gallbladder cancer:a global perspective.J Surg Oncol,2006,93:607-609.
2.Lazcano-Ponce EC,Miquel JF,Munoz N,et al.Epidemiology and molecular pathology of gallbladder cancer.CA Cancer J Clin,2001,51:349-364.
3.Pandey M.Risk factors for gallbladder cancer:A reappraisal.Eur J Cancer Prey,2003,12:15-24.
4.Nandakumar A,Gupta PC,Gangadharan P,et al.Geographic pathology revisited:Development of an atlas of cancer in India.Int J Cancer,2005,116:740-754.
5.Misra S,Chaturvedi A,Misra NC,et al.Carcinoma of the gallbladder.Lancet Oncol,2003,4:167-176.
6.Hsing AW,Gao YT,Devesa SS,et al.Rising incidence of biliary tract cancers in Shanghai,China.Int J Cancer,1998,75:368-370.
7.张薇,项永兵,刘振伟,等.1973-1999年上海市区老年人恶性肿瘤发病趋势分析。中华老年医学杂志,2005,24:701-704.
8.马新源,汪祥辉,雷通海,等.嘉善县恶性肿瘤发病率及动态研究。中国肿瘤,2001,10:378-380.
9.石景森,杨毅军,赵凤林,等.原发性胆囊癌44年诊治的临床回顾。外科理论与实践,2001,6:137-141.
10.Carriaga MT,Henson DE.Liver,gallbladder,extrahepatic bile ducts,and pancreas.Cancer,1995,75:171-190.
11.Cubertafond P,Gainant A,Cucchiaro G.Surgical treatment of 724 carcinomas of the gallbladder.Results of the French Surgical Association Survey.Ann Surg,1994,219:275-280.
12.Wilkinson DS.Carcinoma of the gall-bladder:an experience and review of the literature.Aust NZ J Surg,1995,65:724-727.
13.Wakai T,Shirai Y,Yokoyama N,et al.Early gallbladder carcinoma does not warrant radical resection.Br J Surg,2001,88:675-678.
14.Ito H,Matros E,Brooks DC,et al.Treatment outcomes associated with surgery for gallbladder cancer:a 20-year experience.J Gastrointest Surg,2004,8:183-190.
15.Lowen fels AB,lindstrom CG,Conway MJ.Gall stones and risk of gall bladder cancer.JNCI,1985,75:77-80.
16.Arundhati Rai,Mohapatra SC,Shukla HS.A review of association of dietary factor in gall bladder cancer.IJC,2004,41:147-152.
17.Kumar S,Kumar S,Kumar S.Infection as a risk factor for gallbladder cancer.J Surg Oncol,2006,93:633-639.
18.顾健人.癌基因、抗癌基因和哺乳动物细胞摹因表达调控。基因分子生物学研究进展,上海:上海科学技术出版社,53-63.
19.Shields JM,Pruitt K,McFall A,et al.Understanding Ras:"it ain't over 'til it's over".Trends Cell Biol,2000,10:147-154.
20.Tada M,Yokosuka O,Omata M,et al.Analysis of ras gene mutations in biliary and pancreatic tumors by polymerase chain reaction and direct sequencing.Cancer,1990,66:930-935.
21.Imai M,Hoshi T,Ogawa T.K-ras codon 12 mutations in biliary tract tumors detected by polymerase chain reaction denaturing gradient gel electrophoresis.Cancer,1994,73:2727-2733.
22.Watanabe M,Asaka M,Tanaka J,et al.Point mutation of K-ras gene codon 12 in biliary tract tumors.Gastroenterology,1994,107:1147-1153.
23.Malats N,Porta M,Pinol JL,et al.Ki-ras mutations as a prognostic factor in extrahepatic bile system cancer.J Clin Oncol,1995,13:1679-1686.
24.Ajiki T,Fujimori T,Onoyama H,et al.K-ras gene mutation in gallbladder carcinomas and dysplasia.Gut,1996,38:426-429.
25.Hanada K,Tsuchida A,Iwao T,et al.Gene mutations of K-ras in gallbladder mucosa and gallbladder carcinoma with an anomalous junction of the pancreaticobiliary duct.Am J Gastroenterol,1999,94:1638-1642.
26.Kim SW,Her KH,Jang JY,et al.K-ras oncogene mutation in cancer and precancerous lesions of the gallbladder.J Surg Oncol,2000,75:246-251.
27.Lee CS.Ras p21 protein immunoreactivity and its relationship to p53 expression and prognosis in gallbladder and extrahepatic biliary carcinoma.Eur J Surg Oncol,1997,23:233-237.
28.姚宏,邢惠清,赵玛丽,等.P2lras在胆囊癌前病变和胆囊癌细胞表达的定量研究。临床肝胆病杂志,1996,12:200-202.
29.Dammann R,Li C,Yoon JH,et al.Epigenetic inactivation of a RAS association domain family protein from the lung tumor suppressor locus 3p21.3.Nat Genet,2000,25:315-319.
30.Vavvas D,Li X,Avruch J,et al.Identification of Norel as a potential Ras effector.J Biol Chem,1998,273:5439-5442.
31.Dreijerink K,Braga E,Kuzmin I,et al.The candidate tumor suppressor gene,RASSF1A,from human chromosome 3p21.3 is involved in kidney tumorigenesis.Proc Natl Acad Sci USA,2001,98:7504-7509.
32.van Engeland M,Roemen GM,Brink M,et al.K-ras mutations and RASSF1A promoter methylation in colorectal cancer.Oncogene,2002,21:3792-3795.
33.Takahashi T,Shivapurkar N,Riquelme E,et al.Aberrant promoter hypermethylation of multiple genes in gallbladder carcinoma and chronic cholecystitis.Clin Cancer Res,2004,10:6126-6133.
34.Riquelme E,Tang M,Baez S,et al.Frequent epigenetic inactivation of chromosome 3p candidate tumor suppressor genes in gallbladder carcinoma.Cancer Lett,2007,250:100-106.
35.Adhikary S,Eilers M.Transcriptional regulation and transformation by Myc proteins.Nature Rev Mol Cell,2005,6:635-645.
36.Nesbit CE,Tersak JM,Prochownik EV.Myc oncogenes and human neoplastic disease.Oncogene,1999,18:3004-3016.
37.Lee W,Mitchell P,Tjian R.Purified transcription factor AP-1 interacts with TPA-inducible enhancer elements.Cell,1987,49:741-752.
38.Chiu R,Boyle WJ,Meek J,et al.The c-Fos protein interacts with c-Jun/AP-1 to stimulate transcription of AP-1 responsive genes.Cell,1988,54:541-552.
39.Curran T,Franza BR Jr.Fos and Jun:the AP-1 connection.Cell,1988,55:395-397.
40.Milde-Langosch K.The Fos family of transcription factors and their role in tumourigenesis.Eur J Cancer,2005,41:2449-2461.
41.Yukawa M,Fujimori T,Hirayama D,et al.Expression of oncogene products and growth factors in early gallbladder cancer,advanced gallbladder cancer,and chronic cholecystitis.Hum Pathol,1993,24:37-40.
42.Lee CS.Differences in c-fos gene product expression in cancers of the gall-bladder and biliary tract.Pathol Int,1996,46:771-776.
43.Asano T,Shoda J,Ueda T,et al.Expressions of cyclooxygenase-2 and prostaglandin E-receptors in carcinoma of the gallbladder:crucial role of arachidonate metabolism in tumor growth and progression.Clin Cancer Res,2002,8:1157-1167.
44.Semba K,Kamata N,Toyoshima K,et al.A v-erbB-related protooncogene,c-erbB-2,is distinct from the c-erbB-1/epidermal growth factor-receptor gene and is amplified in a human salivary gland adenocarcinoma.Proc Natl Acad Sci U S A,1985,82:6497-6501.
45.Moasser MM.The oncogene HER2:its signaling and transforming functions and its role in human cancer pathogenesis.Oncogene,2007,26:6469-6487.
46.Suzuki T,Takano Y,Kakita A,et al.An immunohistochemical and molecular biological study of c-erbB-2 amplification and prognostic relevance in gallbladder cancer.Pathol Res Pract,1993,189:283-292.
47.Chow NH,Huang SM,Chan SH,et al.Significance of c-erbB-2 expression in normal and neoplastic epithelium of biliary tract.Anticancer Res,1995,15:1055-1059.
48.Kamel D,Paakk(o|¨) P,Nuorva K,et al.p53 and c-erbB-2 protein expression in adenocarcinomas and epithelial dysplasias of the gall bladder.J Pathol,1993,170:63-72.
49.Matsuyama S,Kitajima Y,Sumi K,et al.Gallbladder cancers rarely overexpress HER-2/neu,demonstrated by Hercep test.Oncol Rep,2004,11:815-819.
50.Nakazawa K,Dobashi Y,Suzuki S,et al.Amplification and overexpression of c-erbB-2,epidermal growth factor receptor,and c-met in biliary tract cancers.J Pathol,2005,206:356-365.
51.王连刚,张惠中.癌基因c-erbB-2在胆囊癌中的异常表达及意义。细胞与分子免疫学杂志,1998,14:105-106.
52.Boudny V,Murakami Y,Nakano S,et al.Expression of activated c-erbB-2 oncogene induces sensitivity to cisplatin in human gallbladder adenocarcinoma cells.Anticancer Res,1999,19:5203-5206.
53. Guvakova MA. Insulin-like growth factors control cell migration in health and disease. Int J Biochem Cell Biol, 2007, 39: 890-909.
54. Leivonen SK, Kahari VM. Transforming growth factor-beta signaling in cancer invasion and metastasis. Int J Cancer, 2007, 121: 2119-2124.
55. Fomchenko EI, Holland EC. Platelet-derived growth factor-mediated gliomagenesis and brain tumor recruitment. Neurosurg Clin N Am, 2007, 18: 39-58.
56. Matsumoto K, Nakamura T. Hepatocyte growth factor and the Met system as a mediator of tumor-stromal interactions. Int J Cancer, 2006, 119: 477-483.
57. Bianco R, Gelardi T, Damiano V, et al. Rational bases for the development of EGFR inhibitors for cancer treatment. Int J Biochem Cell Biol, 2007, 39: 1416-1431.
58. Lee CS, Pirdas A. Epidermal growth factor receptor immunoreactivity in gallbladder and extrahepatic biliary tract tumours. Pathol Res Pract, 1995, 191: 1087-1091.
59. Lee CS. Transforming growth factor alpha immunoreactivity in human gallbladder and extrahepatic biliary tract tumours. Eur J Surg Oncol, 1998, 24: 38-42.
60. Yamamoto S, Kitadai Y, Tsuchida A, et al. Expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase in human gallbladder lesions. Eur J Cancer, 2000, 36: 257-263.
61. Kornprat P, Rehak P, Ruschoff J, et al. Expression of IGF-I, IGF-II, and IGF-IR in gallbladder carcinoma. A systematic analysis including primary and corresponding metastatic tumours. J Clin Pathol, 2006, 59: 202-206.
62. Kaneko K, Ando H, Ito T, et al. Increased cell proliferation and transforming growth factor-alpha (TGF alpha) in the gall-bladder epithelium of patients with pancreaticobiliary maljunction. Pathol Int, 1996, 46: 253-260.
63. Shimura H, Date K, Matsumoto K, et al. Induction of invasive growth in a gallbladder cancer cell line by hepatocyte growth factor in vitro. Jpn J Cancer Res,1995,86:662-669.
64. Li H, Shimura H, Aoki Y, et al. Hepatocyte growth factor stimulates the invasion of gallbladder carcinoma cell lines in vitro. Clin Exp Metastasis, 1998, 16: 74-82.
65. Date K, Matsumoto K, Kuba K, et al. Inhibition of tumor growth and invasion by a four-kringle antagonist (HGF/NK4) for hepatocyte growth factor. Oncogene, 1998,17: 3045-3054.
66.Musgrove EA.Cyclins:roles in mitogenic signaling and oncogenic transformation.Growth Factors,2006,24:13-19.
67.Shapiro GI.Cyclin-dependent kinase pathways as targets for cancer treatment.J Clin Oncol,2006,24:1770-1783.
68.Tashiro E,Tsuchiya A,Imoto M.Functions of cyclin D1 as an oncogene and regulation of cyclin D1 expression.Cancer Sci,2007,98:629-635.
69.Yasmeen A,Berdel WE,Serve H,et al.E-and A-type cyclins as markers for cancer diagnosis and prognosis.Expert Rev Mol Diagn,2003,3:617-633.
70.Berglund P,Landberg G.Cyclin e overexpression reduces infiltrative growth in breast cancer:yet another link between proliferation control and tumor invasion.Cell Cycle,2006,5:606-609.
71.Itoi T,Shinohara Y,Takeda K,et al.Nuclear cyclin D1 overexpression is a critical event associated with cell proliferation and invasive growth in gallbladder carcinogenesis.J Gastroenterol,2000,35:142-149.
72.Hui AM,Li X,Shi YZ,et al.Cyclin D1 overexpression is a critical event in gallbladder carcinogenesis and independently predicts decreased survival for patients with gallbladder carcinoma.Clin Cancer Res,2000,6:4272-4277.
73.Eguchi N,Fujii K,Tsuchida A,et al.Cyclin E overexpression in human gallbladder carcinomas.Oncol Rep,1999,6:93-96.
74.屠金夫,蒋飞照,陈必成.原发性胆囊癌细胞增殖与细胞周期素E表达的关系。中华实验外科杂志,2000,17:20-21.
75.牛坚,陈澍周,钱海鑫.Cyclin E、P27在原发性胆囊癌中表达及临床意义。肝胆胰外科杂志,2004,16:90-92.
76.Bourdon JC.p53 and its isoforms in cancer.Br J Cancer,2007,97:277-282.
77.Buschmann T,Potapova O,Bar-Shira A,et al.Jun NH2-terminal kinase phosphorylation of p53 on Thr-81 is important for p53 stabilization and transcriptional activities in response to stress.Mol Cell Biol,2001,21:2743-2754.
78.Harris SL,Levine AJ.The p53 pathway:Positive and negative feedback loops.Oncogene,2005,24:2899-2908.
79.Efeyan A,Serrano M.p53:guardian of the genome and policeman of the oncogenes.Cell Cycle,2007,6:1006-1010.
80. Palmero I, Pantoja C, Serrano M. p19ARF links the tumour suppressor p53 to Ras. Nature, 1998, 395: 125-126.
81. Wee A, Teh M, Raju GC. Clinical importance of p53 protein in gall bladder carcinoma and its precursor lesions. J Clin Pathol, 1994, 47: 453-456.
82. Hanada K, Itoh M, Fujii K, et al. TP53 mutations in stage I gallbladder carcinoma with special attention to growth patterns. Eur J Cancer, 1997, 33: 1136-1140.
83. Jonas S, Springmeier G, Tauber R, et al. p53 hot-spot mutational analysis in advanced Western gallbladder carcinoma. World J Surg, 1997, 21: 768-772.
84. Chaube A, Tewari M, Garbyal RS, et al. Preliminary study of p53 and c-erbB-2 expression in gallbladder cancer in Indian patients. BMC Cancer, 2006, 6: 126.
85. Chang HJ, Kim SW, Kim YT, et al. Loss of heterozygosity in dysplasia and carcinoma of the gallbladder. Mod Pathol, 1999, 12: 763-769.
86. Quan ZW, Wu K, Wang J, et al. Association of p53, p16, and vascular endothelial growth factor protein expressions with the prognosis and metastasis of gallbladder cancer. J Am Coll Surg, 2001, 193: 380-383.
87. Chang HJ, Yoo BC, Kim SW, et al. Significance of PML and p53 protein as molecular prognostic markers of gallbladder carcinomas. Pathol Oncol Res, 2007, 13:326-335.
88. Kamb A, Gruis NA, Weaver-Feldhaus J, et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science, 1994, 264: 436-440.
89. Canepa ET, Scassa ME, Ceruti JM, et al. INK4 proteins, a family of mammalian CDK inhibitors with novel biological functions. IUBMB Life, 2007, 59: 419-426.
90. Ruas M, Peters G The pl6INK4a/CDKN2A tumor suppressor and its relatives.Biochim Biophys Acta, 1998, 1378: F115-F177.
91. Esteller M, Corn PG, Baylin SB, et al. A gene hypermethylation profile of human cancer. Cancer Res, 2001, 61: 3225-3229.
92. Aggerholm A, Holm MS, Guldberg P, et al. Promoter hypermethylation of p15INK4B, HIC1, CDH1, and ER is frequent in myelodysplastic syndrome and predicts poor prognosis in early-stage patients. Eur J Haematol, 2006, 76: 23-32.
93. Sanchez-Aguilera A, Delgado J, Camacho FI, et al. Silencing of the pl8INK4c gene by promoter hypermethylation in Reed-Sternberg cells in Hodgkin lymphomas. Blood, 2004, 103: 2351-2357.
94. Ortega S, Malumbres M, Barbacid M. Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim Biophys Acta, 2002, 1602: 73-87.
95. EL-Deiry WS, Tokino T, Velculescu VE, et al. WAF1, a potential mediator of p53 tumor suppression. Cell, 1993, 75: 817-825.
96. Rowland BD, Peeper DS. KLF4, p21 and context-dependent opposing forces in cancer. Nat Rev Cancer, 2006, 6: 11-23.
97. Polyak K, Lee MH, Erdjument-Bromage H, et al. Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell, 1994, 78: 59-66.
98. Slingerland J, Pagano M. Regulation of the cdk inhibitor p27Kip1 and its deregulation in cancer. J Cell Physiol, 2000, 183: 10-17.
99. Matsuda Y, Ichida T, Genda T, et al. Loss of p16 contributes to p27 sequestration by cyclin D (1)-cyclin-dependent kinase 4 complexes and poor prognosis in hepatocellular carcinoma. Clin Cancer Res, 2003, 9: 3389-3396.
100.Han J, Tsukada Y, Hara E, et al. Hepatocyte growth factor induces redistribution of p21(CIP1) and p27(KIP1) through ERK-dependent p16(INK4a) up-regulation,leading to cell cycle arrest at Gl in HepG2 hepatoma cells. J Biol Chem, 2005, 280:31548-31556.
101.Kim YT, Kim J, Jang YH, et al. Genetic alterations in gallbladder adenoma, dysplasia and carcinoma. Cancer Lett, 2001, 169: 59-68.
102.Parwani AV, Geradts J, Caspers E, et al. Immunohistochemical and genetic analysis of non-small cell and small cell gallbladder carcinoma and their precursor lesions.Mod Pathol, 2003, 16: 299-308.
103.Ueki T, Hsing AW, Gao YT, et al. Alterations of p16 and prognosis in biliary tract cancers from a population-based study in China. Clin Cancer Res, 2004, 10:1717-1725.
104.Cobrinik D. Pocket proteins and cell cycle control. Oncogene, 2005, 24: 2796-2809.
105.Dimova DK, Dyson NJ. The E2F transcriptional network: Old acquaintances with new faces. Oncogene, 2005, 24: 2810-2826.
106.Mittnacht S. Control of pRB phosphorylation. Curr Opin Genet Dev, 1998, 8: 21-27.
107.Knudsen KE, Diehl JA, Haiman CA, et al. Cyclin D1: Polymorphism, aberrant splicing and cancer risk. Oncogene, 2006, 25: 1620-1628.
108.Xuan YH, Choi YL, Shin YK, et al. An immunohistochemical study of the expression of cell-cycle-regulated proteins p53, cyclin D1, RB, p27, Ki67 and MSH2 in gallbladder carcinoma and its precursor lesions. Histol Histopathol, 2005, 20:59-66.
109.Ma HB, Hu HT, Di ZL, et al. Association of cyclin D1, p16 and retinoblastoma protein expressions with prognosis and metastasis of gallbladder carcinoma. World J Gastroenterol, 2005, 11: 744-747.
110.Shi YZ, Hui AM, Li X, et al. Overexpression of retinoblastoma protein predicts decreased survival and correlates with loss of p16INK4 protein in gallbladder carcinomas. Clin Cancer Res, 2000, 6: 4096-4100.
111.Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science, 1997, 275: 1943-1947.
112.Weng L, Brown J, Eng C. PTEN induces apoptosis and cell cycle arrest through phosphoinositol-3-kinase/Akt-dependent and -independent pathways. Hum Mol Genet, 2001, 10:237-242.
113.Tumura M, Gu J, Takino, et al. Tumor suppressor PTEN inhibition of cell invasion,migration, and growth: differential involvement of focal adhesion kinase and p130~(cas).Cancer Res, 1999, 59: 442-449.
114.Weng LP, SmithWM, Brown TL, et al. PTEN inhibits insulin-stimulated MEK/MAPK activation and cell grovth by blocking IRS21 phosphorylation and IRS21/Grb22/Sos complex formation in a breast model. Hum Mol Genet, 2001, 10:605-616.
115.Groden J, Thliveris A, Samowitz W, et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell, 1991, 66: 589-600.
116.Homma MK, Li D, Krebs EG, et al. Association and regulation of casein kinase 2 activity by adenomatous polyposis coli protein. Proc Natl Acad Sci U S A, 2002, 99:5959-5964.
117.Fearon ER, Cho KR, Nigro JM, et al. Identification of a chromosome 18q gene that is altered in colorectal cancers. Science, 1990, 247: 49-56.
118.Keino-Masu K,Masu M,Hinck L,et al.Deleted in Colorectal Cancer(DCC)encodes a netrin receptor.Cell,1996,75:175-185.
119.Hahn SA,Schutte M,Hoque AT,et al.DPC4,a candidate tumor suppressor gene at human chromosome 18q21.1.Science,1996,271:350-353.
120.Riggins GJ,Kinzler KW,Vogelstein B,et al.Frequency of Smad gene mutations in human cancers.Cancer Res,1997,57:2578-2580.
121.Zawel L,Dai JL,Buckhaults P,et al.Human Smad3 and Smad4 are sequence-specific transcription activators.Mol Cell,1998,1:611-617.
122.李海,吴晓阳,颜鸣.抑癌基因PTEN蛋白在胆囊癌中的表达及临床病理意义。现代肿瘤医学,2006,14:972-974.
123.黄英,郑长黎.原发性胆囊癌中PTEN和P53基因表达的研究。中国癌症杂志,2006,16:547-550.
124.Yoshida T,Sugai T,Habano W,et al.Microsatellite instability in gallbladder carcinoma:two independent genetic pathways of gallbladder carcinogenesis.J Gastroenterot,2000,35:768-774.
125.Takahashi T,Shivapurkar N,Riquelme E,et al.Aberrant promoter hypermethylation of multiple genes in gallbladder carcinoma and chronic cholecystitis.Clin Cancer Res,2004,10:6126-6133.
126.Roa JC,Anabal6n L,Roa I,et al.Promoter methylation profile in gallbladder cancer.J Gastroenterol,2006,41:269-275.
127.Wistuba II,Sugio K,Hung J,et al.Allele-specific mutations involved in the pathogenesis of endemic gallbladder carcinoma in Chile.Cancer Res,1995,55:2511-2515.
128.Chuang SC,Lee KT,Tsai KB,et al.Immunohistochemical study of DPC4 and p53proteins in gallbladder and bile duct cancers.World J Surg,2004,28:995-1000.
129.Cory S,Adams JM.The Bcl2 family:regulators of the cellular life-or-death switch.Nat Rev Cancer,2002,2:647-656.
130.Bakhshi A,Wright JJ,Graninger W,et al.Mechanism of the t(14;18) chromosomal translocation:structural analysis of both derivative 14 and 18 reciprocal partners.Proc Natl Acad Sci USA,1987,84:2396-2400.
131.McDonnell TJ,Korsmeyer SJ.Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14;18). Nature, 1991, 349:254-256.
132.Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature, 1988, 335: 440-442.
133.Bissonnette RP, Echeverri F, Mahboubi A, et al. Apoptotic cell death induced by c-myc is inhibited by bcl-2. Nature, 1992, 359: 552-554.
134.Vander Heiden MG, Li XX, Gottleib E, et al. Bcl-xL promotes the open configuration of the voltage-dependent anion channel and metabolite passage through the outer mitochondrial membrane. J Biol Chem, 2001, 276: 19414-19419.
135.He L, Perkins GA, Poblenz AT, et al. Bcl-xL overexpression blocks bax-mediated mitochondrial contact site formation and apoptosis in rod photoreceptors of lead-exposed mice. Proc Natl Acad Sci U S A, 2003, 100: 1022-1027.
136.Wei MC, Zong WX, Cheng EH, et al. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science, 2001, 292: 727-730.
137.Sasatomi E, Tokunaga O, Miyazaki K. Spontaneous apoptosis in gallbladder carcinoma. Relationships with clinicopathologic factors, expression of E-cadherin,bcl-2 protooncogene, and p53 oncosuppressor gene. Cancer, 1996, 78: 2101-2110.
138.Mikami T, Yanagisawa N, Baba H, et al. Association of Bcl-2 protein expression with gallbladder carcinoma differentiation and progression and its relation to apoptosis.Cancer, 1999,85:318-325.
139.Ariyama H, Qin B, Baba E, et al. Gefitinib, a selective EGFR tyrosine kinase inhibitor, induces apoptosis through activation of Bax in human gallbladder adenocarcinoma cells. J Cell Biochem, 2006, 97: 724-734.
140.Ai Z, Lu W, Qin X. Arsenic trioxide induces gallbladder carcinoma cell apoptosis via downregulation of Bcl-2. Biochem Biophys Res Commun, 2006, 348: 1075-1081.
141.Falschlehner C, Emmerich CH, Gerlach B, et al. TRAIL signalling: decisions between life and death. Int J Biochem Cell Biol, 2007, 39: 1462-1475.
142.Sprick MR, Walczak H. The interplay between the Bcl-2 family and death receptor-mediated apoptosis. Biochim Biophys Acta, 2004, 1644: 125-132.
143.Xu LN, Zou SQ, Wang JM. Action and mechanism of Fas and Fas ligand in immune escape of gallbladder carcinoma. World J Gastroenterol, 2005, 11: 3719-3723.
144.Duffy MJ,O'Donovan N,Brennan DJ,et al.Survivin:a promising tumor biomarker.Cancer Lett,2007,249:49-60.
145.Grossman D,Kim PJ,Blanc-Brude O,et al.Transgenic expression of survivin in keratinocytes counteracts UVB-induced apoptosis and cooperates with loss of p53.J Clin Invest,2001,108:991-999.
146.Pennati M,Colella G,Folini L,et al.Ribozyme-mediated attenuation of surviving expression sensitizes human melanoma cells to cis-platininduced apoptosis.J Clin Invest,2002,109:285-286.
147.Shin BC,Sung BJ,Kim H,et al.An antiapoptotic protein human survivin is a direct inhibitor of caspase-3 and -7.Biochemistry,2001,40:1117-1123.
148.Banks DP,Plescia J,Altieri DC.Survivin does not inhibit caspase-3 activity.Blood,2000,96:4002.
149.Marusawa H,Matsuzawa S,Welsh K,et al.HBXIP functions as a cofactor of surviving in apoptosis suppression.EMBO J,2003,22:2729-2740.
150.Du C,Fang M,Li Y,et al.Smac a mitochondrial protein that promotes cytochrome C-dependent caspase activation by eliminating IAP inhibition.Cell,2000,102:33-42.
151.牛坚,陆艺,钱海鑫.Survivin在原发性胆囊癌中的表达及其临床意义。苏州大学学报·医学版,2006,26:277-278,293.
152.万云乐,丁伟,郑树森,等.原发性胆囊癌Survivin和Ki-67的表达及意义。中华实验外科杂志,2006,23:919-921.
153.沈汉斌,郑启昌.胆囊癌GBC-SD细胞经顺铂处理后的survivin表达及意义。中国普通外科杂志,2007,16:129-132.
154.冯立民,姜希宏,乌新林,等.survivin反义寡核苷酸诱导胆囊癌细胞凋亡的研究。中国普外基础与临床杂志,2006,13:298-301.
155.沈汉斌,郑启昌,王国斌,等.Survivin shRNA表达质粒的构建及其抑制survivin 表达的初步研究。中国普通外科杂志,2006,15:927-931.
156.Liu J,Jiang G.CD44 and hematologic malignancies.Cell Mol Immunol,2006,3:359-365.
157.G(o|¨)tte M,Yip GW.Heparanase,hyaluronan,and CD44 in cancers:a breast carcinoma perspective.Cancer Res,2006,66:10233-10237.
158.Watanabe O,Kinoshita J,Shimizu T,et al.Expression of a CD44 variant and VEGF-C and the implications for lymphatic metastasis and long-term prognosis of human breast cancer.J Exp Clin Cancer Res,2005,24:75-82.
159.Lopez JI,Camenisch TD,Stevens MV,et al.CD44 attenuates metastatic invasion during breast cancer progression.Cancer Res,2005,65:6755-6763.
160.Bourguignon LY,Singleton PA,Zhu H,et al.Hyaluronan-mediated CD44 interaction with RhoGEF and Rho kinase promotes Grb2-associated binder-1 phosphorylation and phosphatidylinositol 3-kinase signaling leading to cytokine(macrophage-colony stimulating factor) production and breast tumor progression.J Biol Chem,2003,278:29420-29434.
161.Yanagisawa N,Mikami T,Mitomi H,et al.CD44 variant overexpression in gallbladder carcinoma associated with tumor dedifferentiation.Cancer,2001,91:408-416.
162.韩玥,石景森,朱爱军,等.胆囊癌中CD44v6和基质金属蛋白酶-2的表达及其临床意义。中国普通外科杂志,2002,11:98-101.
163.谷化平,尚培中,刘艳茹.原发性胆囊癌CD44v6和bcl-2的表达及其与临床病理的关系。中国普外基础与临床杂志,2003,10:46-48.
164.Steeg PS,Bevilacqua G,Kopper L,et al.Evidence for a novel gene associated with low tumor metastatic potential.J Natl Cancer Inst,1988,80:200-204.
165.Sadek CM,Jimenez A,Damdimopoulos AE,et al.Characterization of human thioredoxin-like 2.A novel microtubule-binding thioredoxin expressed predominantly in the cilia of lung airway epithelium and spermatid manchette and axoneme.J Biol Chem,2003,278:13133-13142.
166.Howlett AR,Peterson OW,Steeg PS,et al.A novel function for the nm23-H1 gene:overexpression in human breast carcinoma cells leads to the formation of basement membrane and growth arrest.J Natl Cancer Inst,1994,86:1838-1844.
167.Fan Z,Beresford PJ,Oh DY,et al.Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-mediated apoptosis,and the nucleosome assembly protein SET is its inhibitor.Cell,2003,112:659-672.
168.Ma D,McCorkle JR,Kaetzel DM.The metastasis suppressor NM23-H1 possesses 3'-5' exonuclease activity.J Biol Chem,2004,279:18073-18084.
169.Ouatas T,Salerno M,Palmieri D,et al.Basic and translational advances in cancer metastasis:Nm23.J Bioenerg Biomembr,2003,35:73-79.
170.Fujii K,Yasui W,Shimamoto F,et al.Immunohistochemical analysis of nm23 gene product in human gallbladder carcinomas.Virchows Arch,1995,426:355-359.
171.Lee CS,Pirdas-Zivcic A.nm23-H1 protein immunoreactivity in cancers of the gallbladder,extrahepatic bile ducts and ampulla of Vater.Pathology,1994,26:448-452.
172.韩庆,高寰,康亚安,等.胆囊癌组织中NDPK/nm23的表达及意义。中华普通外科杂志,1997,12:280-282.
173.史朝晖,孙现军,常新忠,等.胆囊癌组织中nm232H1和p16蛋白表达的意义。肿瘤防治杂志,2002,9:597-598.
174.Verma RP,Hansch C.Matrix metalloproteinases(MMPs):chemical-biological functions and(Q)SARs.Bioorg Med Chem,2007,15:2223-2268.
175.Aranapakam V,Grosu GT,Davis JM,et al.Synthesis and structure-activity relationship of alpha-sulfonylhydroxamic acids as novel,orally active matrix metalloproteinase inhibitors for the treatment of osteoarthritis.J Med Chem,2003,46:2361-2375.
176.Venkatesan AM,Davis JM,Grosu GT,et al.Synthesis and structure-activity relationships of 4-alkynyloxy phenyl sulfanyl,sulfinyl,and sulfonyl alkyl hydroxamates as tumor necrosis factor-alpha converting enzyme and matrix metalloproteinase inhibitors.J Med Chem,2004,47:6255-6269.
177.Overall CM,Kleifeld O.Tumour microenvironment-opinion:validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy.Nat Rev Cancer,2006,6:227-239.
178.Bergers G,Brekken R,McMahon G,et al.Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis.Nat Cell Biol,2000,2:737-744.
179.Hofmann UB,Eggert AA,Blass K,et al.Expression of matrix metalloproteinases in the microenvironment of spontaneous and experimental melanoma metastases reflects the requirements for tumor formation.Cancer Res,2003,63:8221-8225.
180.Kido A,Tsutsumi M,Iki K,et al.Overexpression of matrix metalloproteinase (MMP)-9 correlates with metastatic potency of spontaneous and 4-hydroxyaminoquinoline 1-oxide(4-HAQO)-induced transplantable osteosarcomas in rats.Cancer Lett,1999,137:209-216.
181.Agarwal D,Goodison S,Nicholson B,et al.Expression of matrix metalloproteinase 8(MMP-8) and tyrosinaserelated protein-1(TYRP-1) correlates with the absence of metastasis in an isogenic human breast cancer model.Differentiation,2003,71:114-125.
182.McCawley LJ,Crawford HC,King LE,Jr.,et al.A protective role for matrix metalloproteinase-3 in squamous cell carcinoma.Cancer Res,2004,64:6965-6972.
183.Karadag N,Kirimlioglu H,Isik B,et al.Expression of matrix metalloproteinases in gallbladder carcinoma and their significance in carcinogenesis.Appl Immunohistochem Mol Morphol,2008,in press.
184.范跃祖,张景涛.基质金属蛋白酶-2及其组织抑制因子在原发性胆囊癌的表达及意义。中国肿瘤临床,2004,31:675-678.
185.王新保,彭淑牖,郭剑民,等.MMP-7、TIMP-1在胆囊癌组织中的表达。肿瘤防治杂志,2005,14:199-201.
186.牛坚,陈澍周,钱海鑫.TGF-β1和MMP-2在胆囊癌中表达及临床意义。肿瘤防治杂志,2005,12:686-689.
187.Crippa MP.Urokinase-type plasminogen activator.Int J Biochem Cell Biol,2007,39:690-694.
188.Ibanez-Tallon I,Ferrai C,Longobardi E,et al.Binding of Spl to the proximal promoter links constitutive expression of the human uPA gene and invasive potential of PC3 cells.Blood,2002,100:3325-3332.
189.Jankun J,Merrick HW,Goldblatt PJ.Expression and localization of elements of the plasminogen activation system in benign breast disease and breast cancers.J Cell Biochem,1993,53:135-144.
190.Nakajima M,Chop AM.Tumor invasion and extracellular matrix degradative enzymes:regulation of activity by organ factors.Semin Cancer Biol,1991,2:115-127.
191.Alfano D,Iaccarino I,Stoppelli MP.Urokinase signaling through its receptor protects against anoikis by increasing BCL-xL expression levels.J Biol Chem,2006,281:17758-17767.
192.焦兴元,吕明德,黄洁夫,等.胆囊癌患者凝血及纤溶分子标志物的变化研究。肝胆外科杂志,2003,11:349-351.
193.Seo E,Abei M,Wakayama M,et al.Effective gene therapy of biliary tract cancers by a conditionally replicative adenovirus expressing uracil phosphoribosyltransferase:significance of timing of 5-fluorouracil administration.Cancer Res,2005,65:546-552.
194.Tekant Y,Davydova J,Ramirez PJ,et al.Oncolytic adenoviral therapy in gallbladder carcinoma.Surgery,2005,137:527-535.
195.Wu Q,Kiguchi K,Kawamoto T,et al.Therapeutic effect of rapamycin on gallbladder cancer in a transgenic mouse model.Cancer Res,2007,67:3794-3800.
196.靳斌,王伟,姜希宏,等.核酶切割技术对胆囊癌细胞端粒酶活性抑制作用的研究。中国普通外科杂志,2006,15:198-201.
197.丁昂,童赛雄,冯平,等.吲哚美辛和hTERT-siRNA对胆囊癌细胞的作用。复旦学报·医学版,2006,33:614-618.
198.刘刚,仟宏,孙学军,等.脐血源性CIK细胞的体外增殖及其对人胆囊癌细胞株GBC-SD杀伤活性的实验研究。中华肝胆外科杂志,2007,13:540-543.
199.乌新林,董培德,欧阳晓晖,等.野生型p53基因抑制胆囊癌细胞裸鼠体内生长的实验研究。内蒙古医学院学报,2007,29:233-238.
200.逄锦忠,童赛雄,锁涛,等.单纯疱疹病毒胸苷激酶/丙氧鸟苷自杀基因系统对胆囊癌细胞的体外作用。中华实验外科杂志,2004,21:945-947.
201.常新忠,王古民,张毅,等.双自杀基因体系对胆囊癌细胞体内外杀伤作用的研究。中华普通外科杂志,2004,19:631-633.