https://scholars.lib.ntu.edu.tw/handle/123456789/188181
標題: | 尋找與人類肝癌有關的抑癌基因之研究 | 作者: | 許金川 | 關鍵字: | hepatocellular carcinoma;micorsatellite analysis;tumor suppressor gene | 公開日期: | 2002 | 出版社: | 臺北市:國立臺灣大學醫學院內科 | 摘要: | 肝細胞癌是全世界最好發的癌症之一,在台灣也是國人癌症死因的第一位,目前真正的 致病機轉仍不清楚。肝癌的發生通常伴隨基因的變化,其中包括致癌基因的活化、或癌抑制基 因的不活化。目前已知有多種人類腫瘤均與癌抑制基因之變異有關。近年來利用染色體中的微 小衛星可以有系統而快速的分析比較每一染色體中基因的變化,更可進一步尋找可能的癌抑制基因。我們的研究結果顯示肝癌病患在16q 常有雜合子丟失(LOH)的情形,且細微定位的結果 靠近16q12.1,16q21-22 和16q24.3 。因此表示這些位置可能有癌抑制基因的存在。目前,我們 利用位於16q12.1 的標記(D16S415, D16S419, D16S409, D16S3080 及D16S3034) 開始篩選人類 之細菌人工染色體基因庫(Bacterial Artificial Chromosome Library, BAC Library),並配合表現 序列捕捉系統(exon trapping system)找到表現序列的clones 。總共選殖到15 個可能的表現序 列,與NCBI ( national center for Biotechnology Infornation )的資料庫比對的結果,有二個序列 與最近被發現的KIAA1005 基因序列完全相同。而KIAA 1005 基因在肝癌組織中有同源性丟 失的現象,反轉錄-聚合連鎖(T-PCR)的結果也顯示mRNA 的表現有差異,因此我們 推測KIAA1005 基因可能是位於16q12.1 附近的假想抑癌基因。我們進一步分析所選殖基因的 功能發現它具有抑制肝癌細胞生長。另一方面我們利用微陣列晶片分析肝癌,找到一百多個 在肝癌細胞失去調控的基因將進一步分析。 Hepatocellular carcinoma (HCC) is one of the most common cancer in the world and is the leading cause of cancer death in Taiwan. The prognosis of this cancer is extremely poor with survival of only several months after symptoms occurred. Elucidation of the basic genetic changes of HCC is important for the understanding and treatment of this cancer. Cancer is usually accompanied with genetic alternations either through the activation of cellular oncogene or the inactivation of cancer suppressor gene. The recently identified short tandem repeat, the microsatellite, which is widely distributed throughout the whole human genome. Identification of disease genes as well as tumor suppressor genes by microsatellite polymorphism. have been published recently. In this study, we have used 35 microsatellite markers for further fine mapping of LOH. We have confirmed the most frequent regions of LOH for HCC are 16q12.1, 16q22, and 16q24. After analyzing these information, we started to screen the human BAC(Bacterial Artificial chromosome)library by these markers at 16q12.1 and we identified 15 clones. Exon trapping system is used to search the putative exon sequences of BAC genomic clones. Two exon-like sequences are identical to the KIAA1005 gene. Homozygous deletion of KIAA1005 was found in 37%(10 /27) HCCs. These data suggested that the KIAA1005 might be the putative tumor suppressor genes at chromosome 16q12.1. To identify genes involved in the development of familial HCC, we analyzed the transcription profiles of six familial HCC specimens using Human Genome GEM 1 cDNA microarray consisting 9766 elements. Comparison of expression patterns between HCC tumors and the corresponding nontumor tissues made us to identify genes that were commonly upregulated (72 genes) and genes that were downregulated (47 genes) in the tumor cells. Hierarchical clustering analysis of the six familial HCC cases with 119 gene expression ratios demonstrated two distinct expression patterns and might reflect tumors evolved from different liver status. Furthermore, we used laser capture microdissection (LCM) combined with real-time quantitative polymerase chain reaction (RT-QPCR) to confirm microarray data and screen laminin-binding protein and afamin expression levels in two panels of HCC tissues. The expression profiles of 6 familial HCC provided valuable information for elucidation of hepatocarcinogenesis, and revealed the potential biomarkers implicated in this disease. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/23579 | 其他識別: | 902323B002008 | Rights: | 國立臺灣大學醫學院內科 |
顯示於: | 醫學系 |
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