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研究生:黃志賢
研究生(外文):Jhy-Shrian Huang
論文名稱:探討人類肝癌細胞高度表現基因引發細胞轉型能力及其分子機制
論文名稱(外文):Diverse Cellular Transformation Capability of Overexpressed Genes in Human Hepatocellular Carcinomas
指導教授:周玉山周玉山引用關係
指導教授(外文):Yuh-Shan Jou
學位類別:博士
校院名稱:國防醫學院
系所名稱:生命科學研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:80
中文關鍵詞:肝細胞癌無附著生長細胞轉型高度表現
外文關鍵詞:Hepatocellular carcinomaAnchorage-independent growthCellular transformationOverexpressed
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肝細胞癌(hepatocellular carcinomas)是最常見的惡性肝臟腫瘤,其發生率高居世界排名第五,也是台灣十大癌症死因之首。本論文主要目的是想探討肝細胞癌化(hepatocarcinogenesis)的分子機制,利用功能性基因體(functional genomics)研究的方法,找出有關人類肝細胞轉型(cellular transformation)的基因,並了解其所扮演的角色。無附著生長(anchorage-independent growth)是一種細胞外(in vitro)癌化的特徵,我藉此功能性方法從十多種肝癌細胞株中,區分出無附著生長能力強的細胞株PLC5和Huh7與能力弱的細胞株Tong,再經由差異性扣除法(differential subtractive chain)的方式,總共挑出2304個clones,經定序後確定有245個不同的基因,再經由四個不同的標準(criteria),分別是(1)位於癌基因體放大的區域(amplified regions from CGH),(2)反北方點墨法(reverse Northern)的影像強度,(3)即時定量鏈聚合脢(quantitative RT-PCR)反應分析十份肝癌組織中高度表現(overexpression)超過兩倍的比率達到30%,(4)隨機挑出clones的重覆數,而篩選出7個基因。進而利用即時定量鏈聚合脢反應來分析45份肝癌組織,證實這7個基因會高度表現於肝癌組織中,分別是DDX3(64%)、EIF3S2(62%)、CLIC1(60%)、HDGF(58%)、MST4(53%)、GPC3(49%)和HSPCA(47%)。再藉由無附著生長分析,來求證這7個高度表現基因在Tong肝癌細胞株中所引發的細胞轉型 (cellular transformation)能力,EIF3S2具有最強的細胞轉型能力會在軟瓊脂(soft agar)中形成菌落(colony),DDX3、MST4和CLIC1其能力是適中,其次是GPC3和HPCA,HDGF則不會形成任何菌落。由訊息傳遞路徑(signaling pathway)來看導致此現象的差異,在Tong細胞株中可能是STAT3磷酸化(phosphorylation)的傳遞路徑會比PI3K/Akt磷酸化來的重要。
綜合以上所述,此肝癌細胞株Tong是一合適的人類細胞株,可用來篩選高度表現或具有細胞轉型能力的基因。除此之外,本實驗的結果說明肝細胞轉型基因的多樣性(diversity),也潛在性的透露出針對治肝癌新藥開發的標的物。
Hepatocellular carcinomas (HCC) is the fifth most common cancers and the one of the ten major morality causes in Taiwan. The main purpose of this approach is to explore the molecular mechanisms of hepatocarcinogenesis. Using the methodology of functional genomics, I try to find out the genes induced the cellular transformation and to understand their tumorigenic mechanisms of HCC.The ability of anchorage independent growth (AIG) in soft agar is a hallmark of tumorigenicity in vitro. For isolation of novel cellular transforming genes that potentially participated in hepatocarcinogenesis, I conducted AIG assays on 10 human liver cancer cell lines and observed strong AIG capabilities in PLC5 and Huh7 but negligible in Tong cells. After cloning of genes by differential subtractive chain reactions (DSC) from strong AIG to AIG negative cells, I sequenced 2304 clones and identified 245 genes. The 245 genes were further evaluated by the following four stringent criteria including the gene location in amplified HCC genome reported by CGH, increased intensity in AIG positive cells by reverse Northern assays, multiple clones revealed by DSC subtractive cloning and sequencing, and overexpressed in more than 30% of 10 HCC tissues by small-scale quantitative RT-PCR. After four stringent criteria for selection of transforming genes among DSC clones, my results of quantitative RT-PCR analysis indicated that seven genes, DDX3, EIF3S2, CLIC1, HDGF, MST4, GPC3, and HSPCA were overexpressed in 64%, 62%, 60%, 58%, 53%, 49%, and 47%, respectively, of 45 HCC tissues. The results of cellular transformation capability by AIG assays indicated that the transfectants of EIF3S2 showed the strongest (>100-fold), DDX3, MST4 and CLIC1 were moderate, GPC3 and HSPCA were weak, and HDGF was none in forming colonies in soft agar. From the results in dissection of signaling pathways, the phosphorylation of STAT3 pathway is probably more important than that of PI3K/Akt in induction of transformation activity in Tong.
Together, our results suggested that Tong is a suitable human cell line for screening of overexpressed and/or cellular transforming genes. In addition, our results suggested that diverse functions of cellular transforming genes in various biological pathways could transform human Tong cells and potentially reveal new targets for drug development of HC
Introduction................................................1
Importance of hepatocellular carcinomas...................1
Etiology of hepatocellular carcinomas.....................2
Singling transduction involved in hepatocarcinogenesis....4
Genetic and genomic alterations of HCC....................7
Genomic approaches of hepatocarcinogenesis................9
Functional assay of anchorage-independent growth..........11
Methods and Materials.......................................14
Cell lines and tissues....................................14
Soft agar colony formation assay..........................14
Modified differential subtraction chain...................15
Reverse Northern assay by macroarray......................18
Real-Time quantitative RT-PCR analysis....................19
Expression constructs of seven overexpressed genes........21
Transfection and selection of stable clones...............22
Western blot analysis.....................................22
Immunofluorescence staining...............................24
Results.....................................................25
Characterization of HCC cell lines........................25
Identification of a human liver cancer cell line suitable for AIG assay...................................................25
Cloning and sequencing of genes selected by differential subtractive chain reaction..................................26
The seven selected genes overexpressed in HCC tissues by
quantitative RT-PCR.........................................27
Cellular transformation capability of the seven genes overexpressed in Tong.......................................28
Dissection of transformation pathways in various signaling pathways....................................................29
Discussion..................................................32
Conclusion..................................................44
References..................................................46
Appendix....................................................81
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