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研究生(外文):Ji-Ching Lai
論文名稱(外文):The association of induction of ubiquitin overexpression by human papillomavirus 16/18 with lung cancer among nonsmoking Taiwanese women
指導教授:李 輝
指導教授(外文):Huei Lee
外文關鍵詞:ubiquitinHPVlung cancer
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肺癌是台灣地區第一大癌症死亡原因,過去研究指出腫瘤形成通常是經由抑癌基因的突變和蛋白之不穩定而造成去活化所致。過去本研究室已發現肺癌患者發生p53基因的突變頻率遠較其他國家的肺癌為低。同時以免疫組織化學分析法偵測肺腫瘤中p53, p21WAF-1以及Rb蛋白有表現之頻率遠低於過去報告。已知ubiquitin proteasomal pathway參與蛋白的分解,因此本研究擬分析在肺腫瘤形成過程中ubiquitin蛋白是否過度表現而活化ubiquitin proteasomal pathway將p53、p21WAF-1蛋白去活化,因此本研究收集128個肺腫瘤和36個非癌症正常肺組織,以免疫組織染色法分析ubiquitin蛋白在肺組織的表現,結果發現肺癌患者之ubiquitin蛋白僅8個樣品為不表現或低表現,其餘皆為過度表現,而非癌症控制組沒有任何一個樣品為過度表現。因此肺腫瘤組織ubiquitin蛋白表現率明顯高於非癌症控制組 (P=0.001)。並由ubiquitin蛋白與p53、p21WAF-1蛋白表現分析,發現ubiquitin在肺腫瘤組織切片的表現與p53、p21WAF-1蛋白的消失有關,並利用proteasome inhibitor在肺癌細胞 (CL-3) 證實肺癌中p53與p21WAF-1蛋白是經由ubiquitin proteasome pathway所調控。
最近本研究室發現不抽菸女性肺癌患者之人類乳突狀病毒16、18型 (human papillomavirus 16/18, HPV 16/18)感染率顯著高於不抽菸和抽菸男性肺癌患者,同時又發現女性肺癌患者之p53突變頻率不到5%,但p53蛋白有70%無法以免疫染色偵測。因此推測HPV可能誘發ubiquitin蛋白表現,而將p53蛋白分解。故本研究以in situ RT-PCR分析肺癌中HPV 16/18 E6 mRNA表現、ubiquitin蛋白與p53蛋白的消失相關性,結果發現感染HPV 16有E6 mRNA表現的女性肺癌患者經由活化ubiquitin蛋白表現參與p53蛋白之去活化。經由ubiquitin proteosomal pathway來解釋p53蛋白去活化的女性肺癌患者僅有37% (10/27),在沒有HPV 16 E6 mRNA表現,而p53蛋白存在之女性患者有14.8% (4/27),因此可由HPV16感染而表現E6 mRNA的女性患者有一半以上之女性肺癌患者可由E6 活化ubiquitin proteosomal pathway來解釋p53蛋白之去活化。因此ubiquitin在肺腫瘤化過程中過度表現有部分原因是經由HPV感染所致。

Lung cancer is the leading cause of cancer death in Taiwanese women since 1982. Although less than 10% of female lung cancer patients are smokers, high lung cancer mortality ratio of male: female in Taiwan (2:1) was observed. The etiological factor remains unknown. We hypothesize that ubiquitin proteasome system may be associated with lung cancer development based on high prevalence of tumor suppressor gene (p53 or p21WAF-1) negative immunostainings in Taiwanese female lung cancer compared to male lung cancer. In this study, 128 lung tumor cases and 36 non-tumor controls were collected to examine ubiquitin protein expressions by immunohistochemistry. Our data indicated that frequencies of ubiquitin overexpression in lung tumor cases were significantly higher than in non-cancer controls (P=0.0001). To understand whether ubiquitin expression is associated with p53 and p21 inactivation, the immunostaining data of ubiquitin, p53 and p21 were analyzed. The reverse correlation between ubiquitin and p21WAF-1 and/or p53 protein was observed respectively (P=0.006 for p21WAF-1, P=0.237 for p53). To confirm the association, proteasome inhibitor MG-132 was used in lung cancer cell line CL-3 and western blot analysis data showed that p21 and p53 protein levels significantly increased in the addition of proteasome inhibitor MG-132. This result suggests that ubiquitin proteasomal pathway was involved in p21 and p53 protein degradation in lung cancer.
Our recent report indicated that high frequency of HPV 16/18 infection in Taiwanese non-smoking female lung cancer compared to non-smoking and smoking male lung cancer. Our preliminary data showed that high frequency of p53 negative immunostaining in female lung cancer was observed than male lung cancer. We hypothesize that HPV 16/18 E6 protein may be associated with p53 inactivation medicating through ubiquitin proteasomal pathway. Thus, the correlation between HPV 16/18 E6 mRNA expression and p53 immunostaining in lung tumors was statistically analyzed. The correlation was only observed in non-smoking female lung tumors. Our data showed that 10 of 27 (37%) of non-smoking female lung tumors with p53 negative immunostaining had HPV 16 E6 mRNA and ubiquitin positive expressions. On the contrast, 4 of 27 (14.8%) of non-smoking female lung tumors with p53 immunostaining did not have HPV 16 E6 mRNA and ubiquitin expressions. Therefore, high frequencies of p53 negative immunostainings in Taiwanese non-smoking female lung cancer patients may be associated with HPV 16 infection to cause ubiquitin proteasomal pathway activation.

目 錄
壹、中文摘要 1
貳、文獻綜論 3
一、p53抑癌蛋白結構與功能及在肺癌相關研究 3
二、p21WAF-1/CIP-1抑癌基因在結構與功能相關研究 4
三、Ubiquitin proteasome pathway 5
四、人類乳突狀病毒基本介紹 8
五、p53抑癌基因去活化相關研究 11
參、研究動機 14
肆、材料與方法 18
一、腫瘤組織 18
三、組織檢體來源 18
二、材料與藥品 19
四、免疫組織化學染色法 21
五、細胞培養 23
六、蛋白定量與分析 24
七、西方墨點法 24
八、DNA萃取與純化 26
九、基因多型性分析 27
十、統計分析 29
伍、結果與討論 30
一、肺癌與非癌症病患ubiquitin蛋白表現之比較 30
表現之相關性 32
人類乳突狀病毒相關性 36
四、人類乳突狀病毒E6 mRNA對ubiquitin 細胞核
表現相關性 38
五、p21WAF-1抑癌基因與腫瘤相關性 41
陸、參考文獻 44
柒、圖與表 60
捌、英文摘要 81

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