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研究生:吳怡慧
研究生(外文):Yi-Hui
論文名稱:啟動子甲基化造成 XPC 去活化在肺腫瘤化之角色
論文名稱(外文):The role of XPC inactivation by promoter methylation in lung tumor progression
指導教授:李輝李輝引用關係
學位類別:博士
校院名稱:中山醫學大學
系所名稱:醫學分子毒理學研究所
學門:醫藥衛生學門
學類:其他醫藥衛生學類
論文種類:學術論文
論文出版年:2007
畢業學年度:95
語文別:中文
論文頁數:131
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已知 DNA 修補能力 (DRC) 降低與肺癌形成有關,尤其是不抽菸者。XPC是第一個認知 DNA 傷害之 nucleotide excision repair 的蛋白。動物模式研究發現剔除 XPC 基因之小鼠會造成肺腺癌之形成。又知 p53 可做為 XPC 之轉錄因子會促進 XPC 的表現。但是本研究之初步之結果卻發現,既使 p53 發生突變之肺腫瘤組織和肺癌細胞中還是能偵測得到 XPC mRNA 與蛋白的表現,因此推測可能有其他機制參與調控 XPC 基因的表現。本研究假設在肺腫瘤化過程中, XPC 可能會經由啟動子甲基化而降低 DRC,可能會引起 p53 發生突變,進而參與肺癌形成。首先本研究以 reporter assay 證明 XPC 啟動子 -175/-1 序列是主要調控 XPC 基因轉錄之啟動子序列。以 Methylation specific PCR, HpaII-based PCR和 Bisulfite sequencing 三種方法都發現五株 p53 突變或缺失之肺癌細胞中,有四株 (H1355、Calu-1、H441 和 H661) 發生啟動子甲基化。以5-aza-dC去甲基化藥物處理 Calu-1 和 H441 細胞株, XPC mRNA 會重新表現。為了解 XPC 甲基化在肺癌患者與 p53 突變以及與患者臨床因子之相關性,本研究分析 158 位肺癌患者之 XPC 啟動子甲基化,結果 34% 的患者有 XPC 甲基化,其中不抽菸者高達 41%,顯著高於抽菸者 (22%, P = 0.010)。又以 RT-PCR 與免疫染色偵測肺腫瘤之 XPC mRNA 與蛋白表現發現其與 XPC 甲基化呈負相關 (P<0.001),而 XPC mRNA 與其蛋白亦呈正相關 (P<0.001)。本研究發現 p53 突變肺癌患者之 XPC 甲基化的發生頻率較 p53 正常者為高 (42 vs. 28%, P = 0.070)。進一步探討 XPC 去活化是否會造成 p53 發生突變,本研究以 RNAi 方法將 A549 肺癌細胞之 XPC 基因剔除,然後以 1 μM BaP 長時間處理,結果確實找到兩個殖株細胞,在 p53 基因之 codon 215 位置發生突變。本研究為了解 XPC 去活化是否會參與肺腫瘤之轉移而造成患者之預後較差?本研究以 RNAi 技術將 A549 與 CL-1-0 肺癌細胞之 XPC 基因剔除,會造成 p53 與 hHR23B 蛋白降低,而與細胞增生相關之 cyclin D 與 E2F1 蛋白增高,並發現 Skp2 表現會增高而造成 p27kip1 蛋白降解,因而造成 XPC 剔除之 A549 和 CL-1-0 細胞之轉移與侵襲能力增高。本研究以 real-time RT-PCR 分析 128 位肺癌患者之 XPC mRNA 表現量,發現 XPC mRNA 高表現量的肺癌患者之存活率顯著高於 XPC mRNA 低表現者 (40.32 vs. 32.81%,P=0.0440)。以多變項之 Cox’s regression 分析結果發現,XPC mRNA 低表現的罹患肺癌之風險是高表現者的 1.885 倍,此相對風險值 (RR) 和腫瘤期別的 RR 相近,因此 XPC mRNA 表現量適合做為肺癌患者之獨立的臨床預後指標。 總之,本研究發現 XPC 啟動子 -175/-1 序列發生甲基化是抑制 XPC 表現的主要調控機制,而 XPC 去活化可能參與 p53 突變或 p53 蛋白降解而造成細胞的增生,並活化 Skp2 蛋白表現而降解 p27kip1 蛋白造成肺腫瘤惡化。

Reduced DNA repair capability is associated with developing lung cancer, especially in nonsmokers. XPC participates in the initial recognition of DNA damage during the DNA nucleotide excision repair process. Homologous deletion of XPC gene frequently causes lung adenocarcinoma in mice, suggesting that an XPC defect may play a critical role in lung tumorigenesis. p53 has been demonstrated to activate XPC transcription under UV exposure. However, XPC mRNA and protein expressions were detected in lung cancer cells and tumors harbored with p53 mutations. Therefore, transcriptional regulation other than p53 could be involved in XPC transcription. It was hypothesized that inactivation of XPC by promoter hypermethylation may play an important role in the reduction of DNA repair capability to cause p53 mutation during lung carcinogenesis. In this report, it was demonstrated that hypermethylation of 17 CpG islands between –175 and –1 of the XPC promoter correlated very well with XPC expression levels in eight lung cancer cell lines. When cells with hypermethylated XPC promoters were treated with the demethylating agent 5-aza-2`-deoxycytidine, XPC expression was de-repressed. Interestingly, XPC hypermethylation was found in 4 of 5 (80%) lung cancer cell lines harbored p53 mutation (H1355, Calu-1, H441, and H661), but not observed in two lung cancer cells which had a wild-type p53 gene (A549 and CH27). Among the analysis of the hypermethylation status of 158 lung tumors, XPC hypermethylation is more common in nonsmokers (39 of 94, 41%) than in smokers (14 of 64, 22%; P = 0.010). Additionally, XPC hypermethylation is more often with G to T or C mutations in the p53 gene. To verify whether XPC inactivation is involved in the occurrence of p53 mutation, XPC gene of A549 cells was knockdown by a small interference RNA and then XPC-inactivated cells were treated with benzo[a]pynrene for different passages. Surprisingly, G to T mutation in p53 gene at codon 215 was indeed detected in XPC-inactivated A549 cells of passages 15. These results show that hypermethylation of the XPC promoter may play a crucial role in XPC inactivation, which may partly contribute to the occurrence of p53 mutations during lung tumorigenesis, especially nonsmokers. It was further investigated whether reduced XPC mRNA levels predict the clinical outcome of lung cancer patients. The expression of XPC was reduced with increasing invasive potential in A549 and CL-1-0 lung cancer cell lines. When the XPC level was reduced by RNAi, cell migration and invasiveness increased markedly; the increased invasiveness may be caused by decreased expression of p27kip1 and increased expression of skp2. In addition, p53 and hHR23B protein were decreased by proteasomal degradation, and cyclin D and E2F1 were upregulated to promote cell proliferation of XPC knockdown A549 and CL-1-0 cells. To elucidate whether reduced XPC expression correlated with tumor aggressiveness and poor patient survival, XPC mRNA levels were evaluated by real-time RT-PCR. Kaplan-Meier analysis showed that the median survival of patients with lower XPC mRNA levels was shorter compared with patients having higher XPC mRNA levels (P = 0.0440). Cox regression analysis further indicated that XPC mRNA level may act as an independent prognostic factor for non-small cell lung cancer (NSCLC) patients (P = 0.014). Reduced XPC mRNA level may constitute an independent prognostic factor for NSCLC patients. Taken together, XPC inactivation by promoter methylation might not only contribute to p53 mutation during lung tumorigenesis, but also participate to lung tumor invasion.

目 錄

1、中文摘要 1
2、英文摘要 3
3、文獻綜論及緒言 5
3.1 前言 5
3.2 抽菸與肺癌形成之相關性 6
3.3 肺癌形成之分子機轉 7
3.3.1 DNA鍵結物與肺癌形成 7
3.3.2 p53基因突變與肺癌形成 8
3.3.3 Nucleotide excision repair(NER)修補系統與肺癌形成 9
3.3.4 肺腫瘤之啟動子甲基化 (Promoter methylation) 的相關研究 12
3.4 Xeroderma pigmentosum group C (XPC) 基因與肺癌形成 14
3.4.1 XPC 基因起始認知DNA傷害位置 14
3.4.2 XPC 基因在腫瘤形成之角色 15
3.4.3 XPC 基因多型性 (XPC genetic polymorphisms) 15
3.4.4 p53 為 XPC 的轉錄因子 16
3.5 肺腫瘤轉移之現況 17
3.5.1 p53蛋白 18
3.5.2 CRMP-1 與 CTGF 蛋白 19
3.5.3 p27kip1 與 skp2 蛋白 20
3.6 蛋白質降解系統 (Ubiquitin-mediated proteasome pathway) 20
3.6.1 MDM2 22
3.6.2 hHR23B 22
3.6.3 Cullin-dependent ubiquitin ligase 23

4、材料與方法 28
4.1 人類肺癌細胞株來源 28
4.2 組織檢體來源 28
4.3 肺組織RNA萃取 28
4.4 定量RT-PCR (real-time RT-PCR) 28
4.5 肺組織DNA的萃取 29
4.6 p53突變序列分析 30
4.7 自動定序反應的製備 (autosequencer) 30
4.8 XPC promoter片段分析 31
4.9 DNA修補基因之甲基化 ( DNA methylation ) 分析 32
4.10 染色質體免疫沉澱分析 (chromatin immunoprecipitation,CHIP) 33
4.11 XPC抗體製作 35
4.12 免疫組織化學染色(immunohistochemistry IHC)) 37
4.13 XPC-RNA干擾載體的構築 37
4.14 Western blot方法 41
4.15 流式細胞分析儀 (flow cytometry) 42
4.16 XPC基因表現載體的構築 43
4.17 細胞轉移試驗 (Boyden Chamber assay) 45
4.18 統計分析 46
5、結果 47
5.1 XPC 基因甲基化與肺癌形成 47
5.1.1 比較 XPC mRNA 在 p53 突變與沒有突變之肺癌細胞株的表現 47
5.1.2 XPC 基因發生甲基化的位置 47
5.1.3 肺癌細胞株之啟動子甲基化分析 48

5.1.4 以 BaP 處理 XPC 基因缺失的 A549 肺癌細胞會引起 p53 發生突變 50
5.1.5 肺腫瘤組織中 XPC mRNA 和蛋白表現與啟動子甲基化之相關性 52
5.1.6 肺腫瘤組織中 XPC 啟動子甲基化與 p53 基因發生突變之相關性 52
5.2 XPC基因與肺癌轉移 53
5.2.1 XPC 基因對參與細胞週期之蛋白的影響 54
5.2.2 XPC 基因對細胞轉移與侵襲之能力的影響 55
5.2.3 肺癌患者之 XPC mRNA 的表現量與臨床因子之相關性 56
5.2.4 XPC mRNA 表現量可做為肺癌患者之臨床預後指標 56
5.3 XPC 基因缺失造成肺癌轉移之可能機轉 57
6、討論 59
6.1 XPC 基因啟動子甲基化 59
6.1.1 XPC 基因的轉錄調控 59
6.1.2 XPC 啟動子發生甲基化可能之分子機轉 60
6.1.3 XPC 啟動子發生甲基化之可能原因 61
6.2 XPC 去活性的影響 62
6.2.1 XPC 對 p53 的影響 62
6.2.2 XPC 基因對細胞週期的影響 63
6.2.3 XPC 基因對癌細胞轉移與侵襲能力的影響 64
6.2.4 XPC mRNA 可做為肺癌病患之預後指標 65
6.3 蛋白質降解系統在 XPC 去活化過程中可能的角色 66
7、參考文獻 70
8、表與圖 99
9、附錄 131




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