口腔粘膜下纤维性变发病相关基因的筛选与初步鉴定
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摘要
口腔粘膜下纤维性变(oral submucous fibrosis,OSF)是一种慢性、隐匿性、具有癌变倾向的口腔粘膜病,咀嚼槟榔是主要致病因素,OSF属于口腔癌前状态,癌变率高达7.6%。其发病机制目前尚不清楚。基因芯片技术和生物信息学的发展极大提高了我们对生物学研究和探讨疾病分子机制的能力。其高通量、平行、微型化等显著优点已经受到世界各国科学家高度重视,并已广泛用于肿瘤等多个领域研究。本研究采用Affymetrix U133A 2.0芯片构建OSF粘膜组织的基因表达谱;以正常口腔粘膜组织为对照,采用多种生物信息学方法筛选疾病差异表达基因;经逆转录聚合酶链式反应(reverse transcription polymerasechain reation,RT-PCR)对部分候选基因进行了验证,为进一步探讨OSF发生的分子机制和发现治疗靶基因奠定基础。
第一章口腔粘膜下纤维性变差异基因表达分析
[目的]:建立OSF的基因表达谱并筛选其差异表达基因。
[方法]:收集正常和OSF患者颊粘膜组织各4例,提取其总RNA并制备cDNA,合成生物素标记的cRNA探针,经GeneChip Test3验证了探针质量合格后,与Aflymetrix HG-U133A2.0寡核苷酸基因芯片进行杂交,经过洗涤,扫描后用GeneChip Operating Software(GCOS)软件读取每一张芯片探针组中每一位点的表达值,扣除背景信号,自动分析每一基因位点的表达参数并给出参考值,输出数据,并利用dchip2006软件对原始数据进行归一化处理,构建出OSF组织的基因表达谱。再利用基因芯片显著性分析(signficance analysis of microarray,SAM)中两因素不配对算法计算假阳性率,筛选出其OSF差异表达基因。
[结果]:芯片杂交结果符合质量控制要求;按照q-value＜0.05,以fold change＞2或＜0.5为筛选标准,得到OSF差异表达基因共计865个,其中上调基因716个,下调基因149个。
[结论]:在全基因组范围内建立了OSF的基因表达谱并筛选其差异表达基因,为进一步的发病机制研究和寻找OSF分子标记物奠定了基础。
第二章运用生物信息学方法进行差异表达基因的二次筛选
[目的]:运用生物信息学方法分析口腔粘膜下纤维性变差异表达基因,挖掘其隐含的生物学意义。
[方法]:利用多种生物信息学工具和软件对前期筛选的865个OSF差异表达基因进行聚类分析,GO分析、Pathway分析、染色体定位、遗传关联疾病分析和MILANO分析。
[结果]:聚类分析显示所筛选的基因能很好区分正常组与病例组,其中最显著的基因亚类为免疫相关基因。GO分析显示差异表达基因主要参与免疫反应,细胞粘附、炎症反应、DNA依赖的转录调节等生物过程;大部分基因表达蛋白位于细胞外区域、细胞外基质和细胞质膜、膜或整合于膜上。119个基因为未知功能基因,另外有大量的钙铁锌结合分子,其他基因与受体激活和细胞外基质结构构成等分子功能相关;Pathway分析结果显示差异表达基因主要参与抗原过程和呈递、细胞外基质受体相互作用、局部粘附、细胞粘附分子、细胞因子间相互作用、TGF-β信号通路等通路。染色体定位显示差异表达基因主要定位于1、2、5、6、7、11和12号染色体上(P＜0.01);而与这些基因有遗传关联的疾病主要有感染,免疫和心血管疾病等。MILANO分析显示大部分在纤维化疾病和肿瘤中研究广泛的基因在OSF中未曾研究。
[结论]:运用生物信息学工具可快速、平行地分析大量的基因芯片数据,实现对差异基因初步的功能归类,为OSF的发病机制和流行病学研究提供新的思路。
第三章半定量RT-PCR对部分差异表达基因的验证
[目的]:筛选和验证候选基因,并初步探讨其在OSF中的作用。
[方法]:根据多种生物信息学方法和文献复习确定候选基因;抽提11例口腔粘膜下纤维化组织和10例正常口腔粘膜组织的总RNA,通过逆转录聚合酶链式反应检测候选基因在口腔粘膜下纤维性变患者颊粘膜和正常颊粘膜中mRNA的表达。
[结果]:挑选出6个与上皮间质转化(epithelial-mesenchymaltransition,EMT)相关候选基因:sFRP4、THBS1、MMP2、CDH11、ZO-1、CK18。所有的RT-PCR检测表现出与芯片结果一致的变化趋势,统计学处理sFRP4、ZO-1、CK18的P值＜0.01,THBS1和MMP2的P值＜0.05,CDH11的P值＞0.05。
[结论]:基因芯片结果可靠,EMT可能在OSF发病机制中起着重要作用。
Oral submucous Fibrosis(OSF) is a kind of chronic insidious disease and it predisposes to cancer, the main aetiological factor of which is betel nut chewing. As a precancerous condition regarded by WHO, the malignant transformation rate of OSF was 7.6%. The pathogenesis of OSF is still unknown. The development of gene chip technology and bioinformatics boosts greatly our ability of studying biology medicine and exploring the molecular mechanism of diseases. Gene chip technology has become more and more important because of its virtue of high throughput, parallel detection, micromation etc, and it is now widely used in many fields including medical and biological researches.
In this study, we studied the gene expression profiles of human OSF and normal buccal mucosa tissues by using the Affymetrix U133A 2.0 chips, and analyzed the differentially expressed genes of OSF tissues screened by microarray by using several bioinformatics tools. Candidate genes were further validated using semi- quantitative RT-PCR. The results obtained from the present study, therefore, determine the molecular pathways potentially involved in OSF pathogenesis and lay the groundwork for future analysis of these potential markers/targets for clinical utility in the diagnosis, prognosis and treatment of OSF.
Chapter I : Identification of differentially expressed genes associated with oral submucous fibrosis
Objective: To establish the gene expression profiling of OSF and screen differentially expressed genes of OSF.
Material and Methods: Total RNA was isolated from buccal mucosa tissue samples of 4 OSF patients and 4 normal persons. Five ug of total RNA were used to prepare biotinylated cRNAs for hybridization using the standard Affymetrix protocol. After sample quality evaluation using a control microarray (Test 3), the hybridization cocktails were hybridized to the human genome U133A 2.0 GeneChips. After hybridization, washing and scanning, the hybridization data were exported using GeneChip Operating software (GCOS 1.4). The raw signal of individual probes for the 8 arrays were normalized against the chip with median raw signal intensity using the dchip software (dChip2006). Differentially expressed genes were identified by supervised analysis with the Significance Analysis of Microarrays (SAM) software. Normalized expression values from dChip analysis were used for a two class paired SAM analysis. The SAM software estimated the false discovery rate and generated a q value for each gene.
Results: The results of hybridization of GeneChips accorded with the standard of quality control for affymetrix genechip. Using a q value of < 5%, a total of 865 significant probe sets were identified to have more than 2-fold changes between the OSF and normal buccal mucosa tissues. There were 716 up-regulated and 149 down-regulated probe sets in OSF.
Conclusion: The gene expression profiles of OSF were established in whole genome. Differentially expressed genes associated with OSF were identified to provide theoretical foundation for the further studies in the molecular pathogenesis involved in OSF and searching potential biomarkers.
Chapter II: The second Screen of the Differential Expression Genes of OSF using bioinformatics tools
Objective: To apply the bioinformatics tools for analyzing the differentially expressed genes in OSF to obtain the implied biological significance.
Material and Methods: Several bioinformatic analysises were used in the second screening of 865 differentially expressed genes in OSF, which included cluster analysis, gene ontology(GO) analysis, pathway analysis, chromosome location, analysis of genetic-association diseases and MILANO analysis..
Results: Cluster analysis showed the differential expression genes could distinguish OSF from normal tissues perfectly, the most striking subclusters were the immunity-related genes. GO classification of the differentially expressed genes identified the biological process subgroups, including genes involved in immune response, cell adhesion, inflammatory response, regulation of transcription, DNA-dependent et al. Cellular component subgroups consisted of genes mainly located in extracellular region, extracellular matrix and plasma membrane, membrane, integral to membrane. The function of 119 genes remains unkown. The others were mostly related to ion bingding, extracellular matrix structural constituent, receptor activity et el. Pathway analysis suggested the differently expressed genes mainly involved in pathways including antigen processing and presentation, ECM-receptor interaction, focal adhesion, cell adhesion molecules, cytokine-cytokine receptor interaction, TGF-beta signaling pathway et al. A majority of the differentially expressed genes were located on chromosome 1, 2, 5, 6, 7, 11, 12 (P<0.01).The diseases genetic associated with OSF included infection, immune and cardiovascular diseases. MILANO analysis revealed many genes wildly studied in fibrosis and cancer showed occurrences of low frequency in studies of OSF.
Conclusion: Bioinformatic tools can provide the quick and parallel analysis of massive data derived from genechips and enable the function classification of the differentially expressed genes, which provides new clues on the research of pathogenesis and epidemiology of OSF.
Chapter III: Verification of partial differently expressed genes of OSF by semi quantitative RT-PCR
Objective: To valid candidate genes and explore their significance in the pathogenesis of OSF.
Material and Methods: Candidate genes were chosen according to the result of bioinformatics analysis and literature review. The total RNA of 11 specimens of OSF buccal mucosa and 10 specimens of normal mucosa was extracted respectively. The reverse transcription polymerase chain reaction (RT-PCR) was used to examine the levels of mRNA of candidate genes in the buccal mucosa of OSF and normal buccal mucosa.
Results: Six EMT-related genes were chosen to be valid by RT-PCR, which included SFRP4, THBS1, MMP2, CDH11, ZO-1, and CK18. Except for CDH11, the results of RT-PCR showed the consistent trend of change with the results of genechip (P<0.05).
Conclusion: The results of genechip were demonstrated credible. EMT might play an important role in the pathogenesis of OSF.
第一章口腔粘膜下纤维性变差异基因表达分析
[目的]:建立OSF的基因表达谱并筛选其差异表达基因。
[方法]:收集正常和OSF患者颊粘膜组织各4例,提取其总RNA并制备cDNA,合成生物素标记的cRNA探针,经GeneChip Test3验证了探针质量合格后,与Aflymetrix HG-U133A2.0寡核苷酸基因芯片进行杂交,经过洗涤,扫描后用GeneChip Operating Software(GCOS)软件读取每一张芯片探针组中每一位点的表达值,扣除背景信号,自动分析每一基因位点的表达参数并给出参考值,输出数据,并利用dchip2006软件对原始数据进行归一化处理,构建出OSF组织的基因表达谱。再利用基因芯片显著性分析(signficance analysis of microarray,SAM)中两因素不配对算法计算假阳性率,筛选出其OSF差异表达基因。
[结果]:芯片杂交结果符合质量控制要求;按照q-value＜0.05,以fold change＞2或＜0.5为筛选标准,得到OSF差异表达基因共计865个,其中上调基因716个,下调基因149个。
[结论]:在全基因组范围内建立了OSF的基因表达谱并筛选其差异表达基因,为进一步的发病机制研究和寻找OSF分子标记物奠定了基础。
第二章运用生物信息学方法进行差异表达基因的二次筛选
[目的]:运用生物信息学方法分析口腔粘膜下纤维性变差异表达基因,挖掘其隐含的生物学意义。
[方法]:利用多种生物信息学工具和软件对前期筛选的865个OSF差异表达基因进行聚类分析,GO分析、Pathway分析、染色体定位、遗传关联疾病分析和MILANO分析。
[结果]:聚类分析显示所筛选的基因能很好区分正常组与病例组,其中最显著的基因亚类为免疫相关基因。GO分析显示差异表达基因主要参与免疫反应,细胞粘附、炎症反应、DNA依赖的转录调节等生物过程;大部分基因表达蛋白位于细胞外区域、细胞外基质和细胞质膜、膜或整合于膜上。119个基因为未知功能基因,另外有大量的钙铁锌结合分子,其他基因与受体激活和细胞外基质结构构成等分子功能相关;Pathway分析结果显示差异表达基因主要参与抗原过程和呈递、细胞外基质受体相互作用、局部粘附、细胞粘附分子、细胞因子间相互作用、TGF-β信号通路等通路。染色体定位显示差异表达基因主要定位于1、2、5、6、7、11和12号染色体上(P＜0.01);而与这些基因有遗传关联的疾病主要有感染,免疫和心血管疾病等。MILANO分析显示大部分在纤维化疾病和肿瘤中研究广泛的基因在OSF中未曾研究。
[结论]:运用生物信息学工具可快速、平行地分析大量的基因芯片数据,实现对差异基因初步的功能归类,为OSF的发病机制和流行病学研究提供新的思路。
第三章半定量RT-PCR对部分差异表达基因的验证
[目的]:筛选和验证候选基因,并初步探讨其在OSF中的作用。
[方法]:根据多种生物信息学方法和文献复习确定候选基因;抽提11例口腔粘膜下纤维化组织和10例正常口腔粘膜组织的总RNA,通过逆转录聚合酶链式反应检测候选基因在口腔粘膜下纤维性变患者颊粘膜和正常颊粘膜中mRNA的表达。
[结果]:挑选出6个与上皮间质转化(epithelial-mesenchymaltransition,EMT)相关候选基因:sFRP4、THBS1、MMP2、CDH11、ZO-1、CK18。所有的RT-PCR检测表现出与芯片结果一致的变化趋势,统计学处理sFRP4、ZO-1、CK18的P值＜0.01,THBS1和MMP2的P值＜0.05,CDH11的P值＞0.05。
[结论]:基因芯片结果可靠,EMT可能在OSF发病机制中起着重要作用。
Oral submucous Fibrosis(OSF) is a kind of chronic insidious disease and it predisposes to cancer, the main aetiological factor of which is betel nut chewing. As a precancerous condition regarded by WHO, the malignant transformation rate of OSF was 7.6%. The pathogenesis of OSF is still unknown. The development of gene chip technology and bioinformatics boosts greatly our ability of studying biology medicine and exploring the molecular mechanism of diseases. Gene chip technology has become more and more important because of its virtue of high throughput, parallel detection, micromation etc, and it is now widely used in many fields including medical and biological researches.
In this study, we studied the gene expression profiles of human OSF and normal buccal mucosa tissues by using the Affymetrix U133A 2.0 chips, and analyzed the differentially expressed genes of OSF tissues screened by microarray by using several bioinformatics tools. Candidate genes were further validated using semi- quantitative RT-PCR. The results obtained from the present study, therefore, determine the molecular pathways potentially involved in OSF pathogenesis and lay the groundwork for future analysis of these potential markers/targets for clinical utility in the diagnosis, prognosis and treatment of OSF.
Chapter I : Identification of differentially expressed genes associated with oral submucous fibrosis
Objective: To establish the gene expression profiling of OSF and screen differentially expressed genes of OSF.
Material and Methods: Total RNA was isolated from buccal mucosa tissue samples of 4 OSF patients and 4 normal persons. Five ug of total RNA were used to prepare biotinylated cRNAs for hybridization using the standard Affymetrix protocol. After sample quality evaluation using a control microarray (Test 3), the hybridization cocktails were hybridized to the human genome U133A 2.0 GeneChips. After hybridization, washing and scanning, the hybridization data were exported using GeneChip Operating software (GCOS 1.4). The raw signal of individual probes for the 8 arrays were normalized against the chip with median raw signal intensity using the dchip software (dChip2006). Differentially expressed genes were identified by supervised analysis with the Significance Analysis of Microarrays (SAM) software. Normalized expression values from dChip analysis were used for a two class paired SAM analysis. The SAM software estimated the false discovery rate and generated a q value for each gene.
Results: The results of hybridization of GeneChips accorded with the standard of quality control for affymetrix genechip. Using a q value of < 5%, a total of 865 significant probe sets were identified to have more than 2-fold changes between the OSF and normal buccal mucosa tissues. There were 716 up-regulated and 149 down-regulated probe sets in OSF.
Conclusion: The gene expression profiles of OSF were established in whole genome. Differentially expressed genes associated with OSF were identified to provide theoretical foundation for the further studies in the molecular pathogenesis involved in OSF and searching potential biomarkers.
Chapter II: The second Screen of the Differential Expression Genes of OSF using bioinformatics tools
Objective: To apply the bioinformatics tools for analyzing the differentially expressed genes in OSF to obtain the implied biological significance.
Material and Methods: Several bioinformatic analysises were used in the second screening of 865 differentially expressed genes in OSF, which included cluster analysis, gene ontology(GO) analysis, pathway analysis, chromosome location, analysis of genetic-association diseases and MILANO analysis..
Results: Cluster analysis showed the differential expression genes could distinguish OSF from normal tissues perfectly, the most striking subclusters were the immunity-related genes. GO classification of the differentially expressed genes identified the biological process subgroups, including genes involved in immune response, cell adhesion, inflammatory response, regulation of transcription, DNA-dependent et al. Cellular component subgroups consisted of genes mainly located in extracellular region, extracellular matrix and plasma membrane, membrane, integral to membrane. The function of 119 genes remains unkown. The others were mostly related to ion bingding, extracellular matrix structural constituent, receptor activity et el. Pathway analysis suggested the differently expressed genes mainly involved in pathways including antigen processing and presentation, ECM-receptor interaction, focal adhesion, cell adhesion molecules, cytokine-cytokine receptor interaction, TGF-beta signaling pathway et al. A majority of the differentially expressed genes were located on chromosome 1, 2, 5, 6, 7, 11, 12 (P<0.01).The diseases genetic associated with OSF included infection, immune and cardiovascular diseases. MILANO analysis revealed many genes wildly studied in fibrosis and cancer showed occurrences of low frequency in studies of OSF.
Conclusion: Bioinformatic tools can provide the quick and parallel analysis of massive data derived from genechips and enable the function classification of the differentially expressed genes, which provides new clues on the research of pathogenesis and epidemiology of OSF.
Chapter III: Verification of partial differently expressed genes of OSF by semi quantitative RT-PCR
Objective: To valid candidate genes and explore their significance in the pathogenesis of OSF.
Material and Methods: Candidate genes were chosen according to the result of bioinformatics analysis and literature review. The total RNA of 11 specimens of OSF buccal mucosa and 10 specimens of normal mucosa was extracted respectively. The reverse transcription polymerase chain reaction (RT-PCR) was used to examine the levels of mRNA of candidate genes in the buccal mucosa of OSF and normal buccal mucosa.
Results: Six EMT-related genes were chosen to be valid by RT-PCR, which included SFRP4, THBS1, MMP2, CDH11, ZO-1, and CK18. Except for CDH11, the results of RT-PCR showed the consistent trend of change with the results of genechip (P<0.05).
Conclusion: The results of genechip were demonstrated credible. EMT might play an important role in the pathogenesis of OSF.
引文
[1]芷晴.槟榔被认定为一级致癌物.先锋队,2004(05):45
[2]Gupta P C,Ray C S.Epidemiology of betel quid usage.Ann Acad Med Singapore,2004,33(4 Suppl):31-36
[3]Tilakaratne W M,Klinikowski M F,Saku T,et al.Oral submucous fibrosis:Review on aetiology and pathogenesis.Oral Oncol,2005:561-568
[4]Utsunomiya H,Tilakaratne W M,Oshiro K,et al.Extracellular matrix remodeling in oral submucous fibrosis:its stage-specific modes revealed by immunohistochemistry and in situ hybridization.J Oral Pathol Med,2005,34(8):498-507
[5]Tsai C H,Chou M Y,Chang Y C.The up-regulation of cyclooxygenase-2expression in human buccal mucosal fibroblasts by arecoline:a possible role in the pathogenesis of oral submucous fibrosis.J Oral Pathol Med,2003,32(3):146-153
[6]Shieh D H,Chiang L C,Shieh T Y.Augmented mRNA expression of tissue inhibitor of metalloproteinase-1 in buccal mucosal fibroblasts by arecoline and safrole as a possible pathogenesis for oral submucous fibrosis.Oral Oncol,2003,39(7):728-735
[7]李霞.细胞因子与口腔粘膜下纤维性变.国外医学.口腔医学分册,2002(02):25-27
[8]Rajalalitha P,Vali S.Molecular pathogenesis of oral submucous fibrosis--a collagen metabolic disorder.J Oral Pathol Med,2005,34(6):321-328
[9]Ko S Y,Lin S C,Chang K W,et al.Modulation of KGF-1 gene expression in oral fibroblasts by ripe areca nut extract.J Oral Pathol Med,2003,32(7):399-407
[10]Kao W B,Shieh Y D,Hsia Y J,et al.The micro-array analysis of genetic change and proteins identification of oral submucous fibrosis.International Journal of Oral and Maxillofacial Surgery,2005,34(Supplement 1):139-139
[11]The Tumor Analysis Best Practices Working Group.Expression profiling--best practices for data generation and interpretation in clinical trials.Nat Rev Genet,2004,5(3):229-237
[12]张春霆.生物信息学的现状与展望.世界科技研究与发展,2000(06):17-20
[13]Li C,Wong W H.Model-based analysis of oligonucleotide arrays:expression index computation and outlier detection.Proc Natl Acad Sci U S A,2001,98(1):31-36
[14]Han E S,Wu Y,Mccarter R,et al.Reproducibility,sources of variability,pooling, and sample size:important considerations for the design of high-density oligonucleotide array experiments.J Gerontol A Biol Sci Med Sci,2004,59(4):306-315
[15]Qin L X,Beyer R P,Hudson F N,et al.Evaluation of methods for oligonucleotide array data via quantitative real-time PCR.BMC Bioinformatics,2006,7:23
[16]Tusher V G,Tibshirani R,Chu G.Significance analysis of microarrays applied to the ionizing radiation response.Proc Natl Acad Sci U S A,2001,98(9):5116-5121
[17]李小波.基于SAM和GA/SVM的肿瘤基因表达谱分类算法.杭州师范大学学报:自然科学版,2008,7(3):202-205
[18]Trivedy C,Wamakulasuriya K A,Hazarey V K,et al.The upregulation of lysyl oxidase in oral submucous fibrosis and squamous cell carcinoma.J Oral Pathol Med,1999,28(6):246-251
[19]Tsai C H,Yang S F,Chen Y J,et al.The upregulation of insulin-like growth factor-1 in oral submucous fibrosis.Oral Oncol,2005,41(9):940-946
[20]Yang S F,Hsieh Y S,Tsai C H,et al.The upregulation of type I plasminogen activator inhibitor in oral submucous fibrosis.Oral Oncol,2003,39(4):367-372
[21]Liu C J,Lui M T,Chen H L,et al.MICA and MICB overexpression in oral squamous cell carcinoma.J Oral Pathol Med,2007,36(1):43-47
[22]Liu S Y,Lin M H,Yang S C,et al.Areca quid chewing enhances the expression of salivary matrix metalloproteinase-9.J Formos Med Assoc,2005,104(2):113-119
[23]Tsai W C,Tsai S T,Ko J Y,et al.The mRNA profile of genes in betel quid chewing oral cancer patients.Oral Oncol,2004,40(4):418-426
[24]谢辉,凌天牖,郭金陵,等.口腔黏膜下纤维性变发病相关基因的功能分析.口腔医学研究,2007(02)
[25]Brazma A,Hingamp P,Quackenbush J,et al.Minimum information about a microarray experiment(MIAME)-toward standards for microarray data.Nat Genet,2001,29(4):365-371
[26]Ashburner M,Ball C A,Blake J A,et al.Gene ontology:tool for the unification of biology.The Gene Ontology Consortium.Nat Genet,2000,25(1):25-29
[27]Eisen M B,Spellman P T,Brown P O,et al.Cluster analysis and display of genome-wide expression patterns.Proc Natl Acad Sci U S A,1998,95(25):14863-14868
[28]Khatri P,Draghici S,Ostermeier G C,et al.Profiling gene expression using onto-express.Genomics,2002,79(2):266-270
[29]Dennis G J,Sherman B T,Hosack D A,et al.DAVID:Database for Annotation, Visualization,and Integrated Discovery.Genome Biol,2003,4(5):P3
[30]Rubinstein R,Simon I.MILANO--custom annotation of microarray results using automatic literature searches.BMC Bioinformatics,2005,6:12
[31]Chang M C,Chiang C P,Lin C L,et al.Cell-mediated immunity and head and neck cancer:with special emphasis on betel quid chewing habit.Oral Oncol,2005,41(8):757-775
[32]Thiery J P.Epithelial-mesenchymal transitions in development and pathologies.Curr Opin Cell Biol,2003,15(6):740-746
[33]Chang Y C,Tsai C H,Tai K W,et al.Elevated vimentin expression in buccal mucosal fibroblasts by arecoline in vitro as a possible pathogenesis for oral submucous fibrosis.Oral Oncol,2002,38(5):425-430
[34]李霞,凌天牖,高义军.槟榔碱对α平滑肌肌动蛋白在口腔黏膜成纤维细胞中表达的影响.中国现代医学杂志,2007(16)
[35]Nightingale J,Patel S,Suzuki N,et al.Oncostatin M,a cytokine released by activated mononuclear cells,induces epithelial cell-myofibroblast transdifferentiation via Jak/Stat pathway activation.J Am Soc Nephrol,2004,15(1):21-32
[36]Zavadil J,Bottinger E P.TGF-beta and epithelial-to-mesenchymal transitions.Oncogene,2005,24(37):5764-5774
[37]高义军,凌天牖,吴汉江,等.转化生长因子β_1在口腔粘膜下纤维性变角朊细胞中的表达.中华口腔医学杂志,1997(04)
[38]Cromer A,Carles A,Millon R,et al.Identification of genes associated with tumorigenesis and metastatic potential of hypopharyngeal cancer by microarray analysis.Oncogene,2004,23(14):2484-2498
[39]Lin S C,Chen Y J,Kao S Y,et al.Chromosomal changes in betel-associated oral squamous cell carcinomas and their relationship to clinical parameters.Oral Oncol,2002,38(3):266-273
[40]Reshmi S C,Huang X,Schoppy D W,et al.Relationship between FRA11F and 11q13 gene amplification in oral cancer.Genes Chromosomes Cancer,2007,46(2):143-154
[41]Hsu L C,Huang X,Seasholtz S,et al.Gene amplification and overexpression of protein phosphatase lalpha in oral squamous cell carcinoma cell lines.Oncogene,2006,25(40):5517-5526
[42]Tung T H,Chiu Y H,Chen L S,et al.A population-based study of the association between areca nut chewing and type 2 diabetes mellitus in men(Keelung Community-based Integrated Screening programme No.2).Diabetologia,2004,47(10):1776-1781
[43]Chandra P S,Carey M P,Carey K B,et al.Prevalence and correlates of areca nut use among psychiatric patients in India.Drug Alcohol Depend,2003,69(3):311-316
[44]Guh J Y,Chuang L Y,Chen H C.Betel-quid use is associated with the risk of the metabolic syndrome in adults.Am J Clin Nutr,2006,83(6):1313-1320
[45]Thiery J P,Sleeman J P.Complex networks orchestrate epithelial-mesenchymal transitions.Nat Rev Mol Cell Biol,2006,7(2):131-142
[46]Forino M,Torregrossa R,Ceol M,et al.TGFbetal induces epithelial-mesenchymal transition,but not myofibroblast transdifferentiation of human kidney tubular epithelial cells in primary culture.Int J Exp Pathol,2006,87(3):197-208
[47]李秋霞,罗茂林,李茹柳,等.紧密连接蛋白ZO-1研究概述.广州中医药大学学报,2007(06):523-526
[48]Lawler J.The functions of thrombospondin-1 and-2.Curr Opin Cell Biol,2000,12(5):634-640
[49]张璟,周飞舟,邹贵勉.血小板反应蛋白1及血管内皮生长因子在肾间质纤维化中的表达及意义.重庆医学,2007(05):411-413
[50]Neilson E G.Setting a trap for tissue fibrosis.Nat Med,2005,11(4):373-374
[51]赵宗江,李相辉.上皮-间质转化信号转导在肾间质纤维化中机制的研究进展.中国中西医结合肾病杂志,2007(02):113-115
[52]Hugo C.The thrombospondin 1-TGF-beta axis in fibrotic renal disease.Nephrol Dial Transplant,2003,18(7):1241-1245
[53]Murphy-ullrich J E,Poczatek M.Activation of latent TGF-beta by thrombospondin-1:mechanisms and physiology.Cytokine Growth Factor Rev,2000,11(1-2):59-69
[54]罗丽敏,王俐.Wnt通路抑制因子Sfrp的研究进展.医学综述,2007(10):729-731
[55]Chong C C,Stump R J,Lovicu F J,et al.TGFbeta promotes Wnt expression during cataract development.Exp Eye Res,2008
[56]Surendran K,Schiavi S,Hruska K A.Wnt-dependent beta-catenin signaling is activated after unilateral ureteral obstruction,and recombinant secreted frizzled-related protein 4 alters the progression of renal fibrosis.J Am Soc Nephrol,2005,16(8):2373-2384
[57] Cheng S, Pollock A S, Mahimkar R, et al. Matrix metalloproteinase 2 and basement membrane integrity: a unifying mechanism for progressive renal injury. FASEB J,2006,20(11): 1898-1900
[58] Chang Y C, Yang S F, Tai K W, et al. Increased tissue inhibitor of metalloproteinase-1 expression and inhibition of gelatinase A activity in buccal mucosal fibroblasts by arecoline as possible mechanisms for oral submucous fibrosis. Oral Oncol,2002,38(2):195-200
[59] Liu S Y, Lin M H, Yang S C, et al. Increased expression of matrix metalloproteinase-2 in oral cells after short-term stimulation and long-term usage of areca quid. J Formos Med Assoc,2005,104(6):390-397
[60] Jorda M, Olmeda D, Vinyals A, et al. Upregulation of MMP-9 in MDCK epithelial cell line in response to expression of the Snail transcription factor. J Cell Sci,2005,118(Pt 15):3371-3385
[61] Radisky D C, Przybylo J A. Matrix metalloproteinase-induced fibrosis and malignancy in breast and lung. Proc Am Thorac Soc,2008,5(3):316-322
[1] Ranganathan K, Kavitha R, Sawant S S, e. Cytokeratin expression in oral submucous fibrosis-an immunohistochemical study. J Oral Pathol Med,2006,35(1):25-32
[2] Tilakaratne W M, Klinikowski M F, Saku T, e. Oral submucous fibrosis: Review on aetiology and pathogenesis. Oral Oncol,2006,42:561-568
[3] Chiang C P, Hsieh R P, Chen T H, e. High incidence of autoantibodies in Taiwanese patients with oral submucous fibrosis. J Oral Pathol Med,2002,31(7):402-409
[4] Shook D, Keller R. Mechanisms, mechanics and function of epithelial-mesenchymal transitions in early development. Mech Dev,2003,120(11):1351-1383
[5] Iwano M, Plieth D, Danoff T M, e. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest,2002,110(3):341-350
[6] Desmouliere A. Factors influencing myofibroblast differentiation during wound healing and fibrosis. Cell Biol Int,1995,19(5):471-476
[7] Ackland M L, Newgreen D F, Fridman M, e. Epidermal growth factor-induced epithelio-mesenchymal transition in human breast carcinoma cells. Lab Invest,2003,83(3): 435-448
[8] Yang J, Mani S A, Donaher J L, e. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell,2004,117(7):927-939
[9] Grunert S, Jechlinger M, Beug H. Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Nat Rev Mol Cell Biol,2003,4(8):657-665
[10] Okada H, Danoff T M, Kalluri R, e. Early role of Fspl in epithelial-mesenchymal transformation. Am J Physiol, 1997,273(4 Pt 2):563-574
[11] Greenburg G, Hay E D. Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells. J Cell Biol,1982,95(1):333-339
[12] Hay E D. An overview of epithelio-mesenchymal transformation. Acta Anat (Basel),1995,154(1):8-20
[13] Saika S, Kono-saika S, Ohnishi Y, e. Smad3 signaling is required for epithelial-mesenchymal transition of lens epithelium after injury. Am J Pathol,2004,164(2): 651-663
[14] Wu Z, Yang L, Cai L, e. Detection of epithelial to mesenchymal transition in airways of a bleomycin induced pulmonary fibrosis model derived from an alpha-smooth muscle actin-Cre transgenic mouse. Respir Res,2007,8:l
[15] Tahashi Y, Matsuzaki K, Date M, e. Differential regulation of TGF-beta signal in hepatic stellate cells between acute and chronic rat liver injury. Hepatology,2002,35(1):49-61
[16] Neilson E G. Setting a trap for tissue fibrosis. Nat Med,2005,11(4):373-374
[17] Kalluri R, Neilson E G. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest,2003,112(12): 1776-1784
[18] Thiery J P. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer,2002,2(6):442-454
[19] Peinado H, Portillo F, Cano A. Transcriptional regulation of cadherins during development and carcinogenesis. Int J Dev Biol,2004,48(5-6):365-375
[20] Barrallo-gimeno A, Nieto M A. The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development,2005,132(14):3151-3161
[21] Moody S E, Perez D, Pan T C, e. The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell,2005,8(3): 197-209
[22] Petersen 0 W, Nielsen H L, Gudjonsson T, e. Epithelial to mesenchymal transition in human breast cancer can provide a nonmalignant stroma. Am J Pathol,2003,162(2):391-402
[23] Huber M A, Azoitei N, Baumann B, e. NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest,2004,l 14(4):569-581
[24] Yang Y, Zhao S, Song J. Caspase-dependent apoptosis and -independent poly(ADP-ribose) polymerase cleavage induced by transforming growth factor betal. Int J Biochem Cell Biol,2004,36(2):223-234
[25] Ten D P, Goumans M J, Itoh F, e. Regulation of cell proliferation by Smad proteins. J Cell Physiol,2002,191(1): 1-16
[26] Massague J, Wotton D. Transcriptional control by the TGF-beta/Smad signaling system. EMBO J,2000,19(8): 1745-1754
[27] Saika S, Ikeda K, Yamanaka O, e. Transient adenoviral gene transfer of Smad7 prevents injury-induced epithelial-mesenchymal transition of lens epithelium in mice. Lab Invest,2004,84( 10): 1259-1270
[28] Kloth J N, Fleuren G J, Oosting J, e. Substantial changes in gene expression of Wnt, MAPK and TNFalpha pathways induced by TGF-betal in cervical cancer cell lines. Carcinogenesis,2005,26(9):1493-1502
[29] Zeisberg M, Hanai J, Sugimoto H, e. BMP-7 counteracts TGF-betal-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med,2003,9(7):964-968
[30] Zeisberg M, Bottiglio C, Kumar N, e. Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse models. Am J Physiol Renal Physiol,2003,285(6): 1060-1067
[31] Yoshikawa M, Hishikawa K, Marumo T, e. Inhibition of histone deacetylase activity suppresses epithelial-to-mesenchymal transition induced by TGF-betal in human renal epithelial cells. J Am Soc Nephrol,2007,18(l):58-65
[32] Rees J R, Onwuegbusi B A, Save V E, e. In vivo and In vitro Evidence for Transforming Growth Factor-{beta} 1-Mediated Epithelial to Mesenchymal Transition in Esophageal Adenocarcinoma. Cancer Res,2006,66(19):9583-9590
[33] Tan X, Li Y, Liu Y. Therapeutic role and potential mechanisms of active Vitamin D in renal interstitial fibrosis. J Steroid Biochem Mol Biol,2007,103(3-5):491-496
[34] Xavier S, Piek E, Fujii M, e. Amelioration of radiation-induced fibrosis: inhibition of transforming growth factor-beta signaling by halofuginone. J Biol Chem,2004,279(15): 15167-15176
[35] Portella G, Cumming S A, Liddell J, e. Transforming growth factor beta is essential for spindle cell conversion of mouse skin carcinoma in vivo: implications for tumor invasion. Cell Growth Differ,1998,9(5):393-404
[36] Birchmeier C, Birchmeier W, Brand-saberi B. Epithelial-mesenchymal transitions in cancer progression. Acta Anat (Basel),1996,156(3):217-226
[37] Ellenrieder V, Hendler S F, Boeck W, e. Transforming growth factor betal treatment leads to an epithelial-mesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signal-regulated kinase 2 activation. Cancer Res,2001,61(10):4222-4228
[38] Miyazawa J, Mitoro A, Kawashiri S, e. Expression of mesenchyme-specific gene HMGA2 in squamous cell carcinomas of the oral cavity. Cancer Res,2004,64(6):2024-2029
[39] Reeves R, Edberg D D, Li Y. Architectural transcription factor HMGI(Y) promotes tumor progression and mesenchymal transition of human epithelial cells. Mol Cell Biol,2001,21(2):575-594
[40] Mattijssen V, Peters H M, Schalkwijk L, e. E-cadherin expression in head and neck squamous-cell carcinoma is associated with clinical outcome. Int J Cancer, 1993,55(4): 580-585
[41] Yokoyama K, Kamata N, Hayashi E, e. Reverse correlation of E-cadherin and snail expression in oral squamous cell carcinoma cells in vitro. Oral Oncol,2001,37(1):65-71
[42] Maeda G, Chiba T, Okazaki M, e. Expression of SIP1 in oral squamous cell carcinomas: implications for E-cadherin expression and tumor progression. Int J Oncol,2005,27(6): 1535-1541
[43] Comijn J, Berx G, Vermassen P, e. The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell,2001,7(6): 1267-1278
[44] Guaita S, Puig I, Franci C, e. Snail induction of epithelial to mesenchymal transition in tumor cells is accompanied by MUC1 repression and ZEB1 expression. J Biol Chem,2002,277(42):39209-39216
[45] Peinado H, Quintanilla M, Cano A. Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines: mechanisms for epithelial mesenchymal transitions. J Biol Chem,2003,278(23):21113-21123
[46] Taki M, Verschueren K, Yokoyama K, e. Involvement of Ets-1 transcription factor in inducing matrix metalloproteinase-2 expression by epithelial-mesenchymal transition in human squamous carcinoma cells. Int J Oncol,2006,28(2):487-496
[47] Yokoyama K, Kamata N, Fujimoto R, e. Increased invasion and matrix metalloproteinase-2 expression by Snail-induced mesenchymal transition in squamous cell carcinomas. Int J Oncol,2003,22(4):891-898
[48] Taki M, Kamata N, Yokoyama K, e. Down-regulation of Wnt-4 and up-regulation of Wnt-5a expression by epithelial-mesenchymal transition in human squamous carcinoma cells. Cancer Sci,2003,94(7):593-597
[49] Onoue T, Uchida D, Begum N M, e. Epithelial-mesenchymal transition induced by the stromal cell-derived factor-1/CXCR4 system in oral squamous cell carcinoma cells. Int J Oncol,2006,29(5):1133-1138
[50] Grille S J, Bellacosa A, Upson J, e. The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res,2003,63(9):2172-2178
[51] Chung C H, Parker J S, Ely K, e. Gene Expression Profiles Identify Epithelial-to-Mesenchymal Transition and Activation of Nuclear Factor-{kappa}B Signaling as Characteristics of a High-risk Head and Neck Squamous Cell Carcinoma. Cancer Res,2006,66(16):8210-8218
[52] Barker J N, Mitra R S, Griffiths C E, e. Keratinocytes as initiators of inflammation. Lancet,1991,337(8735):211-214
[53] Jeng J H, Hahn L J, Lin B R, e. Effects of areca nut, inflorescence piper betle extracts and arecoline on cytotoxicity, total and unscheduled DNA synthesis in cultured gingival keratinocytes. J Oral Pathol Med,1999,28(2):64-71
[54] Jeng J H, Wang Y J, Chiang B L, e. Roles of keratinocyte inflammation in oral cancer: regulating the prostaglandin E2, interleukin-6 and TNF-alpha production of oral epithelial cells by areca nut extract and arecoline. Carcinogenesis,2003,24(8):1301-1315
[55] Gao Y, Ling T, Wu H. Expression of transforming growth factor beta 1 in keratinocytes of oral submucous fibrosis tissue. Zhonghua Kou Qiang Yi Xue Za Zhi,1997,32(4):239-241
[56] Xu C, Peng X, Liu S. Localization of endothelin-1 in biopsies from oral submucous fibrosis: immunoelectron microscopic study. Zhonghua Kou Qiang Yi Xue Za Zhi,2000,35(3):215-217
[57] Feng Y, Ling T. Changes of cytokines secreted by human oral mucosa keratinocytes from oral submucous fibrosis in vitro. Hua Xi Kou Qiang Yi Xue Za Zhi,2000,18(1):23-25
[58] Rajalalitha P, Vali S. Molecular pathogenesis of oral submucous fibrosis-a collagen metabolic disorder. J Oral Pathol Med,2005,34(6):321-328
[59] Chang M C, Ho Y S, Lee P H, e. Areca nut extract and arecoline induced the cell cycle arrest but not apoptosis of cultured oral KB epithelial cells: association of glutathione, reactive oxygen species and mitochondrial membrane potential. Carcinogenesis,2001,22(9): 1527-1535
[60] Sundqvist K, Grafstrom R C. Effects of areca nut on growth, differentiation and formation of DNA damage in cultured human buccal epithelial cells. Int J Cancer,1992,52(2):305-310
[61] Chang Y C, Tsai C H, Tai K W, e. Elevated vimentin expression in buccal mucosal fibroblasts by arecoline in vitro as a possible pathogenesis for oral submucous fibrosis. Oral Oncol,2002,38(5):425-430
[62] Ranganathan K, Kavitha R, Sawant S S, e. Cytokeratin expression in oral submucous fibrosis-an immunohistochemical study. J Oral Pathol Med,2006,35(1):25-32
[63] Utsunomiya H, Tilakaratne W M, Oshiro K, e. Extracellular matrix remodeling in oral submucous fibrosis: its stage-specific modes revealed by immunohistochemistry and in situ hybridization. J Oral Pathol Med,2005,34(8):498-507
[64] Liu S Y, Lin M H, Yang S C, e. Increased expression of matrix metalloproteinase-2 in oral cells after short-term stimulation and long-term usage of areca quid. J Formos Med Assoc,2005,104(6):390-397
[65] Liu S Y, Lin M H, Yang S C, e. Areca quid chewing enhances the expression of salivary matrix metalloproteinase-9. J Formos Med Assoc,2005,104(2):113-119
[66] Yang S F, Hsieh Y S, Tsai C H, e. Increased plasminogen activator inhibitor-1/tissue type plasminogen activator ratio in oral submucous fibrosis. Oral Dis,2007,13(2):234-238
[67] Haque M F, Harris M, Meghji S, e. Immunolocalization of cytokines and growth factors in oral submucous fibrosis. Cytokine,1998,10(9):713-719
[68] Tsai C H, Yang S F, Chen Y J, e. The upregulation of insulin-like growth factor-1 in oral submucous fibrosis. Oral Oncol,2005,41(9):940-946
[69] Ni W F, Tsai C H, Yang S F, e. Elevated expression of NF-kappaB in oral submucous fibrosis - Evidence for NF-kappaB induction by safrole in human buccal mucosal fibroblasts. Oral Oncol,2006:-1430195913-0
[70] Chen J, Liu Z. Study on the expression of Smad2/3 protein in oral submucous fibrosis. J Clin Stomatol,2006,22(1):43-45
[71] Lin S C, Lu S Y, Lee S Y, e. Areca (betel) nut extract activates mitogen-activated protein kinases and NF-kappaB in oral keratinocytes. Int J Cancer,2005,116(4):526-535
[72] Yang Y, Pan X, Lei W, e. Transforming growth factor-betal induces epithelial-to-mesenchymal transition and apoptosis via a cell cycle-dependent mechanism. Oncogene,2006:7235-7244
[73] Lu S Y, Chang K W, Liu C J, e. Ripe areca nut extract induces G1 phase arrests and senescence-associated phenotypes in normal human oral keratinocyte. Carcinogenesis, 2006,27(6):1273-1284
[74]Yang S C,Lin S C,Chiang W F,e.Areca nut extract treatment elicits the fibroblastoid morphological changes,actin re-organization and signaling activation in oral keratinocytes.J Oral Pathol Med,2003,32(10):600-605
[75]Liu Y.Epithelial to mesenchymal transition in renal fibrogenesis:pathologic significance,molecular mechanism,and therapeutic intervention.J Am Soc Nephrol,2004,15(1):1-12
[76]Miller L D,Long P M,Wong L,e.Optimal gene expression analysis by microarrays.Cancer Cell,2002,2(5):353-361
[77]Long A D,Mangalam H J,Chan B Y,e.Improved statistical inference from DNA microarray data using analysis of variance and a Bayesian statistical framework.Analysis of global gene expression in Escherichia coli K12.J Biol Chem,2001,276(23):19937-19944
[78]Lee M L,Kuo F C,Whitmore G A,e.Importance of replication in microarray gene expression studies:statistical methods and evidence from repetitive cDNA hybridizations.Proc Natl Acad Sci U S A,2000,97(18):9834-9839
[79]Tilstone C.DNA microarrays:vital statistics.Nature,2003,424(6949):610-612
[80]Pavlidis P,Li Q,Noble W S.The effect of replication on gene expression microarray experiments.Bioinformatics,2003,19(13):1620-1627
[81]Hwang D,Schmitt W A,Stephanopoulos G,e.Determination of minimum sample size and discriminatory expression patterns in microarray data.Bioinformatics,2002,18(9):1184-1193
[82]Kendziorski C M,Zhang Y,Lan H,e.The efficiency of pooling mRNA in microarray experiments.Biostatistics,2003,4(3):465-477
[83]Allison D B,Cui X,Page G P,e.Microarray data analysis:from disarray to consolidation and consensus.Nat Rev Genet,2006,7(1):55-65
[84]郭万峰,滕光菊,王升启.几种基因芯片技术的比较.中国生物工程杂志,2004(05):15-19
[85]Tinker A V,Boussioutas A,Bowtell D D.The challenges of gene expression microarrays for the study of human cancer.Cancer Cell,2006,9(5):333-339
[86]敖琳,高利宏,胡冉,等.小鼠毒理基因芯片的可靠性验证.癌变.畸变.突变,2006(02):61-65
[87]Larkin J E,Frank B C,Gavras H,e.Independence and reproducibility across microarray platforms.Nat Methods,2005,2(5):337-344
[88]Irizarry R A,Warren D,Spencer F,e.Multiple-laboratory comparison of microarray platforms.Nat Methods,2005,2(5):345-350
[89]Cui X,Churchill G A.Statistical tests for differential expression in cDNA microarray experiments.Genome Biol,2003,4(4):210
[90]Pawitan Y,Michiels S,Koscielny S,e.False discovery rate,sensitivity and sample size for microarray studies.Bioinformatics,2005,21(13):3017-3024
[91]Zhao Y,Pan W.Modified nonparametric approaches to detecting differentially expressed genes in replicated microarray experiments.Bioinformaties,2003,19(9):1046-1054
[92]Tusher V G,Tibshirani R,Chu G.Significance analysis of microarrays applied to the ionizing radiation response.Proc Natl Acad Sci U S A,2001,98(9):5116-5121
[93]Grant G R,Liu J,Stoeckert C J.A practical false discovery rate approach to identifying patterns of differential expression in microarray data.Bioinformatics,2005,21(11):2684-2690
[94]杨春梅,万柏坤,高晓峰.基因表达聚类分析技术的现状与发展.生物化学与生物物理进展,2003(06):151-156
[95]李杰,唐降龙,王亚东,等.基因表达谱聚类/分类技术研究及展望.生物工程学报,2005(04):161-167
[96]Williams R D,Hing S N,Greer B T,e.Prognostic classification of relapsing favorable histology Wilms tumor using cDNA microarray expression profiling and support vector machines.Genes Chromosomes Cancer,2004,41(1):65-79
[97]Ambroise C,Mclachlan G J.Selection bias in gene extraction on the basis of microarray gene-expression data.Proc Natl Acad Sci U S A,2002,99(10):6562-6566
[98]Fu W J,Carroll R J,Wang S.Estimating misclassification error with small samples via bootstrap cross-validation.Bioinformatics,2005,21(9):1979-1986
[99]Garge N R,Page G P,Sprague A P,e.Reproducible clusters from microarray research:whither? BMC Bioinformatics,2005,6 Suppl 2:S10
[100]Yeung K Y,Medvedovic M,Bumgarner R E.From co-expression to co-regulation:how many microarray experiments do we need? Genome Biol,2004,5(7):R48
[101]Datta S,Datta S.Comparisons and validation of statistical clustering techniques for microarray gene expression data.Bioinformatics,2003,19(4):459-466
[102] Doniger S W, Salomonis N, Dahlquist K D, e. MAPPFinder: using Gene Ontology and GenMAPP to create a global gene-expression profile from microarray data. Genome Biol,2003,4(1):R7
[103] Masseroli M, Galati 0, Pinciroli F. GFINDer: genetic disease and phenotype location statistical analysis and mining of dynamically annotated gene lists. Nucleic Acids Res,2005,33(Web Server issue):717-723
[104] Subramanian A, Tamayo P, Mootha V K, e. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A,2005,102(43): 15545-15550
[105] Patti M E, Butte A J, Crunkhorn S, e. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proc Natl Acad Sci U S A,2003,100(14):8466-8471
[106] Petersen K F, Dufour S, Befroy D, e. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med,2004,350(7): 664-671
[107] Mootha V K, Lindgren C M, Eriksson K F, e. PGC-1 alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet,2003,34(3):267-273
[108] Bild A, Febbo P G. Application of a priori established gene sets to discover biologically important differential expression in microarray data. Proc Natl Acad Sci U S A,2005,102(43): 15278-15279
[2]Gupta P C,Ray C S.Epidemiology of betel quid usage.Ann Acad Med Singapore,2004,33(4 Suppl):31-36
[3]Tilakaratne W M,Klinikowski M F,Saku T,et al.Oral submucous fibrosis:Review on aetiology and pathogenesis.Oral Oncol,2005:561-568
[4]Utsunomiya H,Tilakaratne W M,Oshiro K,et al.Extracellular matrix remodeling in oral submucous fibrosis:its stage-specific modes revealed by immunohistochemistry and in situ hybridization.J Oral Pathol Med,2005,34(8):498-507
[5]Tsai C H,Chou M Y,Chang Y C.The up-regulation of cyclooxygenase-2expression in human buccal mucosal fibroblasts by arecoline:a possible role in the pathogenesis of oral submucous fibrosis.J Oral Pathol Med,2003,32(3):146-153
[6]Shieh D H,Chiang L C,Shieh T Y.Augmented mRNA expression of tissue inhibitor of metalloproteinase-1 in buccal mucosal fibroblasts by arecoline and safrole as a possible pathogenesis for oral submucous fibrosis.Oral Oncol,2003,39(7):728-735
[7]李霞.细胞因子与口腔粘膜下纤维性变.国外医学.口腔医学分册,2002(02):25-27
[8]Rajalalitha P,Vali S.Molecular pathogenesis of oral submucous fibrosis--a collagen metabolic disorder.J Oral Pathol Med,2005,34(6):321-328
[9]Ko S Y,Lin S C,Chang K W,et al.Modulation of KGF-1 gene expression in oral fibroblasts by ripe areca nut extract.J Oral Pathol Med,2003,32(7):399-407
[10]Kao W B,Shieh Y D,Hsia Y J,et al.The micro-array analysis of genetic change and proteins identification of oral submucous fibrosis.International Journal of Oral and Maxillofacial Surgery,2005,34(Supplement 1):139-139
[11]The Tumor Analysis Best Practices Working Group.Expression profiling--best practices for data generation and interpretation in clinical trials.Nat Rev Genet,2004,5(3):229-237
[12]张春霆.生物信息学的现状与展望.世界科技研究与发展,2000(06):17-20
[13]Li C,Wong W H.Model-based analysis of oligonucleotide arrays:expression index computation and outlier detection.Proc Natl Acad Sci U S A,2001,98(1):31-36
[14]Han E S,Wu Y,Mccarter R,et al.Reproducibility,sources of variability,pooling, and sample size:important considerations for the design of high-density oligonucleotide array experiments.J Gerontol A Biol Sci Med Sci,2004,59(4):306-315
[15]Qin L X,Beyer R P,Hudson F N,et al.Evaluation of methods for oligonucleotide array data via quantitative real-time PCR.BMC Bioinformatics,2006,7:23
[16]Tusher V G,Tibshirani R,Chu G.Significance analysis of microarrays applied to the ionizing radiation response.Proc Natl Acad Sci U S A,2001,98(9):5116-5121
[17]李小波.基于SAM和GA/SVM的肿瘤基因表达谱分类算法.杭州师范大学学报:自然科学版,2008,7(3):202-205
[18]Trivedy C,Wamakulasuriya K A,Hazarey V K,et al.The upregulation of lysyl oxidase in oral submucous fibrosis and squamous cell carcinoma.J Oral Pathol Med,1999,28(6):246-251
[19]Tsai C H,Yang S F,Chen Y J,et al.The upregulation of insulin-like growth factor-1 in oral submucous fibrosis.Oral Oncol,2005,41(9):940-946
[20]Yang S F,Hsieh Y S,Tsai C H,et al.The upregulation of type I plasminogen activator inhibitor in oral submucous fibrosis.Oral Oncol,2003,39(4):367-372
[21]Liu C J,Lui M T,Chen H L,et al.MICA and MICB overexpression in oral squamous cell carcinoma.J Oral Pathol Med,2007,36(1):43-47
[22]Liu S Y,Lin M H,Yang S C,et al.Areca quid chewing enhances the expression of salivary matrix metalloproteinase-9.J Formos Med Assoc,2005,104(2):113-119
[23]Tsai W C,Tsai S T,Ko J Y,et al.The mRNA profile of genes in betel quid chewing oral cancer patients.Oral Oncol,2004,40(4):418-426
[24]谢辉,凌天牖,郭金陵,等.口腔黏膜下纤维性变发病相关基因的功能分析.口腔医学研究,2007(02)
[25]Brazma A,Hingamp P,Quackenbush J,et al.Minimum information about a microarray experiment(MIAME)-toward standards for microarray data.Nat Genet,2001,29(4):365-371
[26]Ashburner M,Ball C A,Blake J A,et al.Gene ontology:tool for the unification of biology.The Gene Ontology Consortium.Nat Genet,2000,25(1):25-29
[27]Eisen M B,Spellman P T,Brown P O,et al.Cluster analysis and display of genome-wide expression patterns.Proc Natl Acad Sci U S A,1998,95(25):14863-14868
[28]Khatri P,Draghici S,Ostermeier G C,et al.Profiling gene expression using onto-express.Genomics,2002,79(2):266-270
[29]Dennis G J,Sherman B T,Hosack D A,et al.DAVID:Database for Annotation, Visualization,and Integrated Discovery.Genome Biol,2003,4(5):P3
[30]Rubinstein R,Simon I.MILANO--custom annotation of microarray results using automatic literature searches.BMC Bioinformatics,2005,6:12
[31]Chang M C,Chiang C P,Lin C L,et al.Cell-mediated immunity and head and neck cancer:with special emphasis on betel quid chewing habit.Oral Oncol,2005,41(8):757-775
[32]Thiery J P.Epithelial-mesenchymal transitions in development and pathologies.Curr Opin Cell Biol,2003,15(6):740-746
[33]Chang Y C,Tsai C H,Tai K W,et al.Elevated vimentin expression in buccal mucosal fibroblasts by arecoline in vitro as a possible pathogenesis for oral submucous fibrosis.Oral Oncol,2002,38(5):425-430
[34]李霞,凌天牖,高义军.槟榔碱对α平滑肌肌动蛋白在口腔黏膜成纤维细胞中表达的影响.中国现代医学杂志,2007(16)
[35]Nightingale J,Patel S,Suzuki N,et al.Oncostatin M,a cytokine released by activated mononuclear cells,induces epithelial cell-myofibroblast transdifferentiation via Jak/Stat pathway activation.J Am Soc Nephrol,2004,15(1):21-32
[36]Zavadil J,Bottinger E P.TGF-beta and epithelial-to-mesenchymal transitions.Oncogene,2005,24(37):5764-5774
[37]高义军,凌天牖,吴汉江,等.转化生长因子β_1在口腔粘膜下纤维性变角朊细胞中的表达.中华口腔医学杂志,1997(04)
[38]Cromer A,Carles A,Millon R,et al.Identification of genes associated with tumorigenesis and metastatic potential of hypopharyngeal cancer by microarray analysis.Oncogene,2004,23(14):2484-2498
[39]Lin S C,Chen Y J,Kao S Y,et al.Chromosomal changes in betel-associated oral squamous cell carcinomas and their relationship to clinical parameters.Oral Oncol,2002,38(3):266-273
[40]Reshmi S C,Huang X,Schoppy D W,et al.Relationship between FRA11F and 11q13 gene amplification in oral cancer.Genes Chromosomes Cancer,2007,46(2):143-154
[41]Hsu L C,Huang X,Seasholtz S,et al.Gene amplification and overexpression of protein phosphatase lalpha in oral squamous cell carcinoma cell lines.Oncogene,2006,25(40):5517-5526
[42]Tung T H,Chiu Y H,Chen L S,et al.A population-based study of the association between areca nut chewing and type 2 diabetes mellitus in men(Keelung Community-based Integrated Screening programme No.2).Diabetologia,2004,47(10):1776-1781
[43]Chandra P S,Carey M P,Carey K B,et al.Prevalence and correlates of areca nut use among psychiatric patients in India.Drug Alcohol Depend,2003,69(3):311-316
[44]Guh J Y,Chuang L Y,Chen H C.Betel-quid use is associated with the risk of the metabolic syndrome in adults.Am J Clin Nutr,2006,83(6):1313-1320
[45]Thiery J P,Sleeman J P.Complex networks orchestrate epithelial-mesenchymal transitions.Nat Rev Mol Cell Biol,2006,7(2):131-142
[46]Forino M,Torregrossa R,Ceol M,et al.TGFbetal induces epithelial-mesenchymal transition,but not myofibroblast transdifferentiation of human kidney tubular epithelial cells in primary culture.Int J Exp Pathol,2006,87(3):197-208
[47]李秋霞,罗茂林,李茹柳,等.紧密连接蛋白ZO-1研究概述.广州中医药大学学报,2007(06):523-526
[48]Lawler J.The functions of thrombospondin-1 and-2.Curr Opin Cell Biol,2000,12(5):634-640
[49]张璟,周飞舟,邹贵勉.血小板反应蛋白1及血管内皮生长因子在肾间质纤维化中的表达及意义.重庆医学,2007(05):411-413
[50]Neilson E G.Setting a trap for tissue fibrosis.Nat Med,2005,11(4):373-374
[51]赵宗江,李相辉.上皮-间质转化信号转导在肾间质纤维化中机制的研究进展.中国中西医结合肾病杂志,2007(02):113-115
[52]Hugo C.The thrombospondin 1-TGF-beta axis in fibrotic renal disease.Nephrol Dial Transplant,2003,18(7):1241-1245
[53]Murphy-ullrich J E,Poczatek M.Activation of latent TGF-beta by thrombospondin-1:mechanisms and physiology.Cytokine Growth Factor Rev,2000,11(1-2):59-69
[54]罗丽敏,王俐.Wnt通路抑制因子Sfrp的研究进展.医学综述,2007(10):729-731
[55]Chong C C,Stump R J,Lovicu F J,et al.TGFbeta promotes Wnt expression during cataract development.Exp Eye Res,2008
[56]Surendran K,Schiavi S,Hruska K A.Wnt-dependent beta-catenin signaling is activated after unilateral ureteral obstruction,and recombinant secreted frizzled-related protein 4 alters the progression of renal fibrosis.J Am Soc Nephrol,2005,16(8):2373-2384
[57] Cheng S, Pollock A S, Mahimkar R, et al. Matrix metalloproteinase 2 and basement membrane integrity: a unifying mechanism for progressive renal injury. FASEB J,2006,20(11): 1898-1900
[58] Chang Y C, Yang S F, Tai K W, et al. Increased tissue inhibitor of metalloproteinase-1 expression and inhibition of gelatinase A activity in buccal mucosal fibroblasts by arecoline as possible mechanisms for oral submucous fibrosis. Oral Oncol,2002,38(2):195-200
[59] Liu S Y, Lin M H, Yang S C, et al. Increased expression of matrix metalloproteinase-2 in oral cells after short-term stimulation and long-term usage of areca quid. J Formos Med Assoc,2005,104(6):390-397
[60] Jorda M, Olmeda D, Vinyals A, et al. Upregulation of MMP-9 in MDCK epithelial cell line in response to expression of the Snail transcription factor. J Cell Sci,2005,118(Pt 15):3371-3385
[61] Radisky D C, Przybylo J A. Matrix metalloproteinase-induced fibrosis and malignancy in breast and lung. Proc Am Thorac Soc,2008,5(3):316-322
[1] Ranganathan K, Kavitha R, Sawant S S, e. Cytokeratin expression in oral submucous fibrosis-an immunohistochemical study. J Oral Pathol Med,2006,35(1):25-32
[2] Tilakaratne W M, Klinikowski M F, Saku T, e. Oral submucous fibrosis: Review on aetiology and pathogenesis. Oral Oncol,2006,42:561-568
[3] Chiang C P, Hsieh R P, Chen T H, e. High incidence of autoantibodies in Taiwanese patients with oral submucous fibrosis. J Oral Pathol Med,2002,31(7):402-409
[4] Shook D, Keller R. Mechanisms, mechanics and function of epithelial-mesenchymal transitions in early development. Mech Dev,2003,120(11):1351-1383
[5] Iwano M, Plieth D, Danoff T M, e. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest,2002,110(3):341-350
[6] Desmouliere A. Factors influencing myofibroblast differentiation during wound healing and fibrosis. Cell Biol Int,1995,19(5):471-476
[7] Ackland M L, Newgreen D F, Fridman M, e. Epidermal growth factor-induced epithelio-mesenchymal transition in human breast carcinoma cells. Lab Invest,2003,83(3): 435-448
[8] Yang J, Mani S A, Donaher J L, e. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell,2004,117(7):927-939
[9] Grunert S, Jechlinger M, Beug H. Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Nat Rev Mol Cell Biol,2003,4(8):657-665
[10] Okada H, Danoff T M, Kalluri R, e. Early role of Fspl in epithelial-mesenchymal transformation. Am J Physiol, 1997,273(4 Pt 2):563-574
[11] Greenburg G, Hay E D. Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells. J Cell Biol,1982,95(1):333-339
[12] Hay E D. An overview of epithelio-mesenchymal transformation. Acta Anat (Basel),1995,154(1):8-20
[13] Saika S, Kono-saika S, Ohnishi Y, e. Smad3 signaling is required for epithelial-mesenchymal transition of lens epithelium after injury. Am J Pathol,2004,164(2): 651-663
[14] Wu Z, Yang L, Cai L, e. Detection of epithelial to mesenchymal transition in airways of a bleomycin induced pulmonary fibrosis model derived from an alpha-smooth muscle actin-Cre transgenic mouse. Respir Res,2007,8:l
[15] Tahashi Y, Matsuzaki K, Date M, e. Differential regulation of TGF-beta signal in hepatic stellate cells between acute and chronic rat liver injury. Hepatology,2002,35(1):49-61
[16] Neilson E G. Setting a trap for tissue fibrosis. Nat Med,2005,11(4):373-374
[17] Kalluri R, Neilson E G. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest,2003,112(12): 1776-1784
[18] Thiery J P. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer,2002,2(6):442-454
[19] Peinado H, Portillo F, Cano A. Transcriptional regulation of cadherins during development and carcinogenesis. Int J Dev Biol,2004,48(5-6):365-375
[20] Barrallo-gimeno A, Nieto M A. The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development,2005,132(14):3151-3161
[21] Moody S E, Perez D, Pan T C, e. The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell,2005,8(3): 197-209
[22] Petersen 0 W, Nielsen H L, Gudjonsson T, e. Epithelial to mesenchymal transition in human breast cancer can provide a nonmalignant stroma. Am J Pathol,2003,162(2):391-402
[23] Huber M A, Azoitei N, Baumann B, e. NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest,2004,l 14(4):569-581
[24] Yang Y, Zhao S, Song J. Caspase-dependent apoptosis and -independent poly(ADP-ribose) polymerase cleavage induced by transforming growth factor betal. Int J Biochem Cell Biol,2004,36(2):223-234
[25] Ten D P, Goumans M J, Itoh F, e. Regulation of cell proliferation by Smad proteins. J Cell Physiol,2002,191(1): 1-16
[26] Massague J, Wotton D. Transcriptional control by the TGF-beta/Smad signaling system. EMBO J,2000,19(8): 1745-1754
[27] Saika S, Ikeda K, Yamanaka O, e. Transient adenoviral gene transfer of Smad7 prevents injury-induced epithelial-mesenchymal transition of lens epithelium in mice. Lab Invest,2004,84( 10): 1259-1270
[28] Kloth J N, Fleuren G J, Oosting J, e. Substantial changes in gene expression of Wnt, MAPK and TNFalpha pathways induced by TGF-betal in cervical cancer cell lines. Carcinogenesis,2005,26(9):1493-1502
[29] Zeisberg M, Hanai J, Sugimoto H, e. BMP-7 counteracts TGF-betal-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med,2003,9(7):964-968
[30] Zeisberg M, Bottiglio C, Kumar N, e. Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse models. Am J Physiol Renal Physiol,2003,285(6): 1060-1067
[31] Yoshikawa M, Hishikawa K, Marumo T, e. Inhibition of histone deacetylase activity suppresses epithelial-to-mesenchymal transition induced by TGF-betal in human renal epithelial cells. J Am Soc Nephrol,2007,18(l):58-65
[32] Rees J R, Onwuegbusi B A, Save V E, e. In vivo and In vitro Evidence for Transforming Growth Factor-{beta} 1-Mediated Epithelial to Mesenchymal Transition in Esophageal Adenocarcinoma. Cancer Res,2006,66(19):9583-9590
[33] Tan X, Li Y, Liu Y. Therapeutic role and potential mechanisms of active Vitamin D in renal interstitial fibrosis. J Steroid Biochem Mol Biol,2007,103(3-5):491-496
[34] Xavier S, Piek E, Fujii M, e. Amelioration of radiation-induced fibrosis: inhibition of transforming growth factor-beta signaling by halofuginone. J Biol Chem,2004,279(15): 15167-15176
[35] Portella G, Cumming S A, Liddell J, e. Transforming growth factor beta is essential for spindle cell conversion of mouse skin carcinoma in vivo: implications for tumor invasion. Cell Growth Differ,1998,9(5):393-404
[36] Birchmeier C, Birchmeier W, Brand-saberi B. Epithelial-mesenchymal transitions in cancer progression. Acta Anat (Basel),1996,156(3):217-226
[37] Ellenrieder V, Hendler S F, Boeck W, e. Transforming growth factor betal treatment leads to an epithelial-mesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signal-regulated kinase 2 activation. Cancer Res,2001,61(10):4222-4228
[38] Miyazawa J, Mitoro A, Kawashiri S, e. Expression of mesenchyme-specific gene HMGA2 in squamous cell carcinomas of the oral cavity. Cancer Res,2004,64(6):2024-2029
[39] Reeves R, Edberg D D, Li Y. Architectural transcription factor HMGI(Y) promotes tumor progression and mesenchymal transition of human epithelial cells. Mol Cell Biol,2001,21(2):575-594
[40] Mattijssen V, Peters H M, Schalkwijk L, e. E-cadherin expression in head and neck squamous-cell carcinoma is associated with clinical outcome. Int J Cancer, 1993,55(4): 580-585
[41] Yokoyama K, Kamata N, Hayashi E, e. Reverse correlation of E-cadherin and snail expression in oral squamous cell carcinoma cells in vitro. Oral Oncol,2001,37(1):65-71
[42] Maeda G, Chiba T, Okazaki M, e. Expression of SIP1 in oral squamous cell carcinomas: implications for E-cadherin expression and tumor progression. Int J Oncol,2005,27(6): 1535-1541
[43] Comijn J, Berx G, Vermassen P, e. The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell,2001,7(6): 1267-1278
[44] Guaita S, Puig I, Franci C, e. Snail induction of epithelial to mesenchymal transition in tumor cells is accompanied by MUC1 repression and ZEB1 expression. J Biol Chem,2002,277(42):39209-39216
[45] Peinado H, Quintanilla M, Cano A. Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines: mechanisms for epithelial mesenchymal transitions. J Biol Chem,2003,278(23):21113-21123
[46] Taki M, Verschueren K, Yokoyama K, e. Involvement of Ets-1 transcription factor in inducing matrix metalloproteinase-2 expression by epithelial-mesenchymal transition in human squamous carcinoma cells. Int J Oncol,2006,28(2):487-496
[47] Yokoyama K, Kamata N, Fujimoto R, e. Increased invasion and matrix metalloproteinase-2 expression by Snail-induced mesenchymal transition in squamous cell carcinomas. Int J Oncol,2003,22(4):891-898
[48] Taki M, Kamata N, Yokoyama K, e. Down-regulation of Wnt-4 and up-regulation of Wnt-5a expression by epithelial-mesenchymal transition in human squamous carcinoma cells. Cancer Sci,2003,94(7):593-597
[49] Onoue T, Uchida D, Begum N M, e. Epithelial-mesenchymal transition induced by the stromal cell-derived factor-1/CXCR4 system in oral squamous cell carcinoma cells. Int J Oncol,2006,29(5):1133-1138
[50] Grille S J, Bellacosa A, Upson J, e. The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res,2003,63(9):2172-2178
[51] Chung C H, Parker J S, Ely K, e. Gene Expression Profiles Identify Epithelial-to-Mesenchymal Transition and Activation of Nuclear Factor-{kappa}B Signaling as Characteristics of a High-risk Head and Neck Squamous Cell Carcinoma. Cancer Res,2006,66(16):8210-8218
[52] Barker J N, Mitra R S, Griffiths C E, e. Keratinocytes as initiators of inflammation. Lancet,1991,337(8735):211-214
[53] Jeng J H, Hahn L J, Lin B R, e. Effects of areca nut, inflorescence piper betle extracts and arecoline on cytotoxicity, total and unscheduled DNA synthesis in cultured gingival keratinocytes. J Oral Pathol Med,1999,28(2):64-71
[54] Jeng J H, Wang Y J, Chiang B L, e. Roles of keratinocyte inflammation in oral cancer: regulating the prostaglandin E2, interleukin-6 and TNF-alpha production of oral epithelial cells by areca nut extract and arecoline. Carcinogenesis,2003,24(8):1301-1315
[55] Gao Y, Ling T, Wu H. Expression of transforming growth factor beta 1 in keratinocytes of oral submucous fibrosis tissue. Zhonghua Kou Qiang Yi Xue Za Zhi,1997,32(4):239-241
[56] Xu C, Peng X, Liu S. Localization of endothelin-1 in biopsies from oral submucous fibrosis: immunoelectron microscopic study. Zhonghua Kou Qiang Yi Xue Za Zhi,2000,35(3):215-217
[57] Feng Y, Ling T. Changes of cytokines secreted by human oral mucosa keratinocytes from oral submucous fibrosis in vitro. Hua Xi Kou Qiang Yi Xue Za Zhi,2000,18(1):23-25
[58] Rajalalitha P, Vali S. Molecular pathogenesis of oral submucous fibrosis-a collagen metabolic disorder. J Oral Pathol Med,2005,34(6):321-328
[59] Chang M C, Ho Y S, Lee P H, e. Areca nut extract and arecoline induced the cell cycle arrest but not apoptosis of cultured oral KB epithelial cells: association of glutathione, reactive oxygen species and mitochondrial membrane potential. Carcinogenesis,2001,22(9): 1527-1535
[60] Sundqvist K, Grafstrom R C. Effects of areca nut on growth, differentiation and formation of DNA damage in cultured human buccal epithelial cells. Int J Cancer,1992,52(2):305-310
[61] Chang Y C, Tsai C H, Tai K W, e. Elevated vimentin expression in buccal mucosal fibroblasts by arecoline in vitro as a possible pathogenesis for oral submucous fibrosis. Oral Oncol,2002,38(5):425-430
[62] Ranganathan K, Kavitha R, Sawant S S, e. Cytokeratin expression in oral submucous fibrosis-an immunohistochemical study. J Oral Pathol Med,2006,35(1):25-32
[63] Utsunomiya H, Tilakaratne W M, Oshiro K, e. Extracellular matrix remodeling in oral submucous fibrosis: its stage-specific modes revealed by immunohistochemistry and in situ hybridization. J Oral Pathol Med,2005,34(8):498-507
[64] Liu S Y, Lin M H, Yang S C, e. Increased expression of matrix metalloproteinase-2 in oral cells after short-term stimulation and long-term usage of areca quid. J Formos Med Assoc,2005,104(6):390-397
[65] Liu S Y, Lin M H, Yang S C, e. Areca quid chewing enhances the expression of salivary matrix metalloproteinase-9. J Formos Med Assoc,2005,104(2):113-119
[66] Yang S F, Hsieh Y S, Tsai C H, e. Increased plasminogen activator inhibitor-1/tissue type plasminogen activator ratio in oral submucous fibrosis. Oral Dis,2007,13(2):234-238
[67] Haque M F, Harris M, Meghji S, e. Immunolocalization of cytokines and growth factors in oral submucous fibrosis. Cytokine,1998,10(9):713-719
[68] Tsai C H, Yang S F, Chen Y J, e. The upregulation of insulin-like growth factor-1 in oral submucous fibrosis. Oral Oncol,2005,41(9):940-946
[69] Ni W F, Tsai C H, Yang S F, e. Elevated expression of NF-kappaB in oral submucous fibrosis - Evidence for NF-kappaB induction by safrole in human buccal mucosal fibroblasts. Oral Oncol,2006:-1430195913-0
[70] Chen J, Liu Z. Study on the expression of Smad2/3 protein in oral submucous fibrosis. J Clin Stomatol,2006,22(1):43-45
[71] Lin S C, Lu S Y, Lee S Y, e. Areca (betel) nut extract activates mitogen-activated protein kinases and NF-kappaB in oral keratinocytes. Int J Cancer,2005,116(4):526-535
[72] Yang Y, Pan X, Lei W, e. Transforming growth factor-betal induces epithelial-to-mesenchymal transition and apoptosis via a cell cycle-dependent mechanism. Oncogene,2006:7235-7244
[73] Lu S Y, Chang K W, Liu C J, e. Ripe areca nut extract induces G1 phase arrests and senescence-associated phenotypes in normal human oral keratinocyte. Carcinogenesis, 2006,27(6):1273-1284
[74]Yang S C,Lin S C,Chiang W F,e.Areca nut extract treatment elicits the fibroblastoid morphological changes,actin re-organization and signaling activation in oral keratinocytes.J Oral Pathol Med,2003,32(10):600-605
[75]Liu Y.Epithelial to mesenchymal transition in renal fibrogenesis:pathologic significance,molecular mechanism,and therapeutic intervention.J Am Soc Nephrol,2004,15(1):1-12
[76]Miller L D,Long P M,Wong L,e.Optimal gene expression analysis by microarrays.Cancer Cell,2002,2(5):353-361
[77]Long A D,Mangalam H J,Chan B Y,e.Improved statistical inference from DNA microarray data using analysis of variance and a Bayesian statistical framework.Analysis of global gene expression in Escherichia coli K12.J Biol Chem,2001,276(23):19937-19944
[78]Lee M L,Kuo F C,Whitmore G A,e.Importance of replication in microarray gene expression studies:statistical methods and evidence from repetitive cDNA hybridizations.Proc Natl Acad Sci U S A,2000,97(18):9834-9839
[79]Tilstone C.DNA microarrays:vital statistics.Nature,2003,424(6949):610-612
[80]Pavlidis P,Li Q,Noble W S.The effect of replication on gene expression microarray experiments.Bioinformatics,2003,19(13):1620-1627
[81]Hwang D,Schmitt W A,Stephanopoulos G,e.Determination of minimum sample size and discriminatory expression patterns in microarray data.Bioinformatics,2002,18(9):1184-1193
[82]Kendziorski C M,Zhang Y,Lan H,e.The efficiency of pooling mRNA in microarray experiments.Biostatistics,2003,4(3):465-477
[83]Allison D B,Cui X,Page G P,e.Microarray data analysis:from disarray to consolidation and consensus.Nat Rev Genet,2006,7(1):55-65
[84]郭万峰,滕光菊,王升启.几种基因芯片技术的比较.中国生物工程杂志,2004(05):15-19
[85]Tinker A V,Boussioutas A,Bowtell D D.The challenges of gene expression microarrays for the study of human cancer.Cancer Cell,2006,9(5):333-339
[86]敖琳,高利宏,胡冉,等.小鼠毒理基因芯片的可靠性验证.癌变.畸变.突变,2006(02):61-65
[87]Larkin J E,Frank B C,Gavras H,e.Independence and reproducibility across microarray platforms.Nat Methods,2005,2(5):337-344
[88]Irizarry R A,Warren D,Spencer F,e.Multiple-laboratory comparison of microarray platforms.Nat Methods,2005,2(5):345-350
[89]Cui X,Churchill G A.Statistical tests for differential expression in cDNA microarray experiments.Genome Biol,2003,4(4):210
[90]Pawitan Y,Michiels S,Koscielny S,e.False discovery rate,sensitivity and sample size for microarray studies.Bioinformatics,2005,21(13):3017-3024
[91]Zhao Y,Pan W.Modified nonparametric approaches to detecting differentially expressed genes in replicated microarray experiments.Bioinformaties,2003,19(9):1046-1054
[92]Tusher V G,Tibshirani R,Chu G.Significance analysis of microarrays applied to the ionizing radiation response.Proc Natl Acad Sci U S A,2001,98(9):5116-5121
[93]Grant G R,Liu J,Stoeckert C J.A practical false discovery rate approach to identifying patterns of differential expression in microarray data.Bioinformatics,2005,21(11):2684-2690
[94]杨春梅,万柏坤,高晓峰.基因表达聚类分析技术的现状与发展.生物化学与生物物理进展,2003(06):151-156
[95]李杰,唐降龙,王亚东,等.基因表达谱聚类/分类技术研究及展望.生物工程学报,2005(04):161-167
[96]Williams R D,Hing S N,Greer B T,e.Prognostic classification of relapsing favorable histology Wilms tumor using cDNA microarray expression profiling and support vector machines.Genes Chromosomes Cancer,2004,41(1):65-79
[97]Ambroise C,Mclachlan G J.Selection bias in gene extraction on the basis of microarray gene-expression data.Proc Natl Acad Sci U S A,2002,99(10):6562-6566
[98]Fu W J,Carroll R J,Wang S.Estimating misclassification error with small samples via bootstrap cross-validation.Bioinformatics,2005,21(9):1979-1986
[99]Garge N R,Page G P,Sprague A P,e.Reproducible clusters from microarray research:whither? BMC Bioinformatics,2005,6 Suppl 2:S10
[100]Yeung K Y,Medvedovic M,Bumgarner R E.From co-expression to co-regulation:how many microarray experiments do we need? Genome Biol,2004,5(7):R48
[101]Datta S,Datta S.Comparisons and validation of statistical clustering techniques for microarray gene expression data.Bioinformatics,2003,19(4):459-466
[102] Doniger S W, Salomonis N, Dahlquist K D, e. MAPPFinder: using Gene Ontology and GenMAPP to create a global gene-expression profile from microarray data. Genome Biol,2003,4(1):R7
[103] Masseroli M, Galati 0, Pinciroli F. GFINDer: genetic disease and phenotype location statistical analysis and mining of dynamically annotated gene lists. Nucleic Acids Res,2005,33(Web Server issue):717-723
[104] Subramanian A, Tamayo P, Mootha V K, e. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A,2005,102(43): 15545-15550
[105] Patti M E, Butte A J, Crunkhorn S, e. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proc Natl Acad Sci U S A,2003,100(14):8466-8471
[106] Petersen K F, Dufour S, Befroy D, e. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med,2004,350(7): 664-671
[107] Mootha V K, Lindgren C M, Eriksson K F, e. PGC-1 alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet,2003,34(3):267-273
[108] Bild A, Febbo P G. Application of a priori established gene sets to discover biologically important differential expression in microarray data. Proc Natl Acad Sci U S A,2005,102(43): 15278-15279