臺灣博碩士論文加值系統

摘要
肝癌是目前世界上發生率排名第六位的惡性腫瘤，尤其在熱帶非洲與東南亞最為嚴重。 在台灣肝細胞癌(hepatocellular carcinoma, HCC)是十大癌症之首，每年有超過六千人因此失去生命。 為了能夠進一步了解它的致病機制，本實驗的目的在搜尋可能與肝癌有關的抑癌基因(tumor suppressor genes, TSG )。 由先前對肝細胞癌病人的全基因體缺失搜尋實驗中，我們已經找到了33個高頻率缺失區域(minimal deletion region)。 為了進一步縮小搜尋抑癌基因的範圍，我們利用位於高頻率缺失區域中的微衛星標記(microsatellite marker)來搜尋肝細胞癌細胞株的同質缺失序列(homozygous deletion, HD)。 結果在一株肝細胞癌細胞株SK-Hep-1中，我們發現一段位於13q12.11的同質缺失序列。 這個區域經由高密度的序列標籤標記(STS marker)分析判定大小為1.8Mb，並利用南方轉漬法(Southern blotting)確認這段缺失。 經由進一步的研究發現，在我們的48個病人中有52%在13q12.11具有缺失，而且缺失好發在早發性病人身上(p=0.0023)。 為了搜尋可能的抑癌基因，我們自基因體資料庫中搜集76個位於同質缺失序列的推測基因。 經由比對基因資訊、基因序列以及在癌症組織的表現，我們選出十個推測基因來做細胞生長、遷移(migration)及無附著生長(anchorage independent growth, AIG)的抑癌功能測試。 其中MPP8、IL17D 及TG737 被證實具有抑制無附著生長的能力，而GJB2則可以抑制細胞生長與遷移。 綜合以上所述，我們證明了13q12.11的缺失區域是個可能的抑癌區域，且好發在早發性肝細胞癌病人上,可能可以用來做為臨床診斷之用。 此外經由比較基因的表現及抑癌功能的測試我們也證明了在13q12.11上的GJB2、MPP8、IL17D 及TG737是可能的抑癌基因，值得我們做更深入的研究。

Abstract
Liver cancer is the sixth most common cancer worldwide especially in tropical Africa and south-east Asia. In Taiwan, hepatocellular carcinoma (HCC) is the leading cause of cancer-related mortality in the past decades. For revealing therapeutic and diagnostic targets in HCC treatment, we decided to search and clone cancer genes involved in HCC tumorgenesis. In our laboratory, we previously reported genome-wide loss of heterozygosity (LOH) analysis in HCC genome and revealed 33 minimal deletion regions (MDRs). To further identify putative tumor suppressor genes (TSGs), a homozygous deletion (HD) screening in HCC cell lines was processed by scanning the MDRs. A novel 1-cM (1.8Mb) homozygous deletion (HD) on 13q12.11 was identified in a HCC cell line, SK-Hep-1, and confirmed by high-density genetic markers and Southern blotting analysis. After increasing microsatellite marker density on 13q12.11 for LOH analysis, the frequency of this HD region is 52% in 48 HCC patients. Interestingly, the occurrence of LOH in 13q12.11 HD region is significantly associated with early-onset HCC patients by Mann-Whitney test (P=0.023). Since the HD region is a gene-rich area, 76 transcripts were predicted in the HD by the combination of prediction in NCBI, EnsEMBL and Vega databases. Firstly, 17 known or predicted genes were selected to analyze the information of transcripts, blast the sequence in various databases, and then compare the expression of these 17 candidates in more than 20 HCC tissue pairs. Ten of these genes exhibited down-regulation in HCC tissue were applied to assay their function of tumor suppression including cell growth, migration and anchorage independent growth (AIG) assays. Finally, MPP8, IL17D and TG737 were showed to inhibit the colony formation in AIG assay and GJB2 was identified to control both cell growth and migration. Our results and previous genetic studies provided lines of evidence to support that the HD region on 13q12.11 is a novel tumor suppressor locus for HCC. The results of gene expression analysis and functional assays identified TG737, IL17D, MPP8 and GJB2 are potential TSGs in the HD region.

Contents
Contents I
List of Tables II
List of Figures III
Chinese Abstract V
English Abstract VII
Introduction 1
Chapter I. Identification of Homozygous Deletion at 13q12.11 in SK-Hep-1
Cell 5 Introduction 6
Material and Methods 9
Results 13
Discussion 15
Chapter II. Positional Cloning of Candidate TSGs in 13q12.11 HD
region of Hepatocellular Carcinoma 21
Introduction 22
Material and Methods 23
Results 33
Discussion 38
Conclusion 42
Perspective 43
References 46

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