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研究生:賴吉慶
研究生(外文):Ji-Ching
論文名稱:肺腫瘤化過程中雌性素與 p53 對 O6-甲基鳥嘌呤DNA甲基轉移酶與雌性素受體基因之啟動子甲基化之影響
論文名稱(外文):The impact of 17β-estradiol and p53 status on promoter hypermethylation of O6-methylguanine-DNA methyltransferase and estrogen receptor genes during lung tumorigenesis
指導教授:李 輝
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:138
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已知乳癌、子宮內膜癌和前列腺癌之腫瘤化與ER 啟動子甲基化有關,但是 ER 啟動子甲基化在肺腫瘤化的角色,尤其是 ER 甲基化是否能做為肺癌之臨床預後因子,至今仍不清楚。本研究收集 123 位肺癌患者之腫瘤組織和周邊正常組織以 Methylation specific PCR (MSP) 和RT-PCR分析ER 啟動子之甲基化和其mRNA之表現,結果發現 ER 甲基化僅發生在腫瘤組織,而幾乎不會發生於周圍正常組織,這結果顯示 ER 甲基化可能參與肺腫瘤之形成。而ER甲基化與患者之臨床因子之相關性分析上,僅發現在女性患者之 ER 甲基化低於男性患者 (58 vs. 34%, P = 0.01)。而其他臨床因子均無相關性。為了解雌性素是否是造成 ER 甲基化在性別之差異?本研究以 1與10 nM 雌性素處理 ER 甲基化與 ER mRNA 不表現之 A549 肺癌細胞,結果發現雌性素會促進醯基化組織蛋白 H3 與 H4 之表現,而增加醯基化組織蛋白 H3、H4 與 ER 啟動子含量和降低 DNMT1 和 HDAC1 與啟動子結合活性,因此ER 啟動子去甲基化,並造成 ER mRNA 重新表現。。Kaplan-Meier 分析發現具有ER甲基化患者較沒有甲基化患者之預後較差,但是此預後之臨床意義僅在男性可觀察到 (P = 0.0044),而無法在女性患者見到。進一步以Cox regression 分析發現,ER 啟動子甲基化可做為肺癌之獨立臨床預後指標 (P = 0.007)。因此推測抗雌性素藥用於肺癌臨床治療之效果,可能有男、女性之差異。
本研究的第二部分在探討雌性素是否會如參與 ER 去甲基化一樣造成MGMT去甲基化?本研究將兩株具有 MGMT 甲基化之 Ch27 和 H1355 肺癌細胞分別處理雌性素和去甲基化藥物 (5-AZA-dC),結果發現雌性素與 5-AZA-dC 一樣會造成 MGMT 去甲基化和增加其mRNA 的表現。核染質免疫沈澱聚合酶連鎖反應結果顯示乙醯化之 H3 和 H4 組織蛋白會增加,而HDAC1, DNMT1 和 DNMT3b 結合到MGMT 啟動子之活性降低。因此雌性素確實會改變染色質之重組而造成 MGMT 去甲基化。本研究同樣以 MSP 分析 220 位肺癌患者之MGMT 的甲基化,結果發現男性、鱗狀上皮癌、抽菸者及 p53 突變患者之 MGMT 甲基化頻率較女性、腺癌、不抽菸者和 p53正常者為高。多變項邏輯統計分析的結果顯示性別與p53突變是主要影響MGMT啟動子甲基化之主要因素,有趣的是,女性具有p53突變的患者之MGMT甲基化,顯著低於男性患者 (40 vs. 70%, P = 0.011)。總之,雌性素會調控 MGMT甲基化可能是造成女性患者有較男性患者有低之 MGMT 甲基化和p53基因突變頻率的部分原因。本研究發現晚期肺癌患者同時發生MGMT 甲基化與 p53 突變之頻率顯著高於早期患者,因此假設 p53 可能會參與 MGMT 甲基化。本研究以 RNAi 技術將 A549 細胞剔除 p53 基因,另外將正常 p53 或轉譯子 194 突變之 p53 轉染於 H1299 細胞中,來分析 MGMT 啟動子之甲基化和其 mRNA 的表現是否會改變?結果發現 正常 p53 會抑制 DNMT1 與 HDAC1 轉錄表現,可能經由降低 DNMT1、HDAC1 與 MGMT 啟動子結合以及增加醯基化 H3、H4 蛋白而造成 MGMT 啟動子去甲基化和其 mRNA 表現。反之,p53 突變或缺失之細胞則會維持或造成 MGMT 啟動子之甲基化,而抑制其 mRNA 的表現。因此 p53 確實會經由調控染色質重組之相關蛋白而造成 MGMT 啟動子甲基化或去甲基化。總之,不僅 p53 會調控啟動子之甲基化,同時雌性素亦會透過相同之機制來調控 ER 和 MGMT 啟動子之甲基化,而調控該基因的轉錄活性,進而參與肺癌之形成。


The estrogen receptor (ER) transcription silencing due to hypermethylation has been documented to link with the tumor progression of breast, uterine, and prostate cancers. However, the role of hypermethylation-induced ER transcription silencing in lung tumor progression, and its prognostic value for non-small cell lung cancer (NSCLC) patients remained unclear. In the present study, ER hypermethylation of 123 lung tumors and adjacent normal parts were examined by methylation-specific PCR (MSP), and ER mRNA expression in lung tumors were determined by reverse-transcription PCR (RT-PCR). Our data indicated that ER promoter methylation was only detected in lung tumors, but not in adjacent normal lung tissues, suggesting that ER hypermethylation may be associated with lung tumorigenesis. Among those studied clinical parameters, only gender factor was correlated with ER hypermethylation with a higher frequency of ER methylation being in male cases than in female cases (58 vs. 34%, P = 0.01). To investigate if 17-beta estradiol (E2) was responsible for such gender difference in ER hypermethylation, a lung cancer A549 cell line with ER hypermethylation and without ER mRNA expression was treated with E2 of various concentrations to show that an E2 treatment could restore the expression of ER mRNA and eliminate ER methylation. Western blot data also showed that the level of acetylated histone 3 and histone 4 of chromatin were significantly increased by E2 treatment. Thus, E2 could repress ER methylation to restore ER mRNA expression. Kaplan-Meier analysis showed that patients with ER methylation had a poorer survival than those without ER methylation. However, such prognostic value only observed in male (P = 0.0044), not in female. Cox regression analysis further revealed that ER methylation may be an independent prognostic factor of NSCLC (P = 0.007). It was therefore possible that antiestrogens may have different therapeutic values for male and female lung cancer patients.
In the second part of the study, it was speculated that E2 might exert a similar demethylation effect on MGMT hypermethylation to restore MGMT transcription. To elucidate whether E2 could modulate MGMT methylation, two types of lung cancer cells, Ch27 and H1355, with MGMT hypermethylation were treated with E2 in comparison with a demethylation agent 5-AZA-dC. Results showed that E2 had an effect, similar to that of 5-AZA-dC, to diminish the MGMT hypermethylation and restore MGMT mRNA expression. The bisulfite sequencing showed the methylated CpG islands to be almost demethylated by E2 in both cell lines. Chromatin immunoprecipitation (CHIP) analysis further revealed that E2 increased the acetylation of H3 and H4 histones and decreased the binding activity of HDAC, DNMT1 and DNMT3b. These results suggested that E2 modulated MGMT hypermethylation to restore its mRNA expression in lung cancer cells. Furthermore, a total of 220 lung tumors, from 152 male and 68 female patients, were collected to examine MGMT hypermethylation by MSP. Our data indicated that the frequency of MGMT hypermethylation in female, adenocarcinomas, and nonsmokers patient group was lower than that of male, squamous cell carcinomas, and smokers. Multivariate logistic regression analysis revealed that MGMT hypermethylation was predominately influenced by gender factor and p53 mutation among various clinical parameters. Interestingly, MGMT hypermethylation in female with p53 mutation had a lower prevalence than that of male (40 vs. 71%, P = 0.011). Taken together, MGMT hypermethylation modulated by E2 might contribute to the gender difference in MGMT hypermethylation and the occurrence of p53 mutation. MGMT promoter methylation is more common in advanced tumors with mutant p53 than in early tumors with mutant p53. However, in tumors with wild-type p53, MGMT promoter methylation is independent of tumor stage. To elucidate whether p53 participates in MGMT promoter methylation, three cell lines were engineered: A549 cells with RNA interference (RNAi)-mediated knockdown of p53, and p53 null H1299 cells transfected with either wild-type p53 (WT-p53) or mutant-p53 (L194R-p53). Knockdown of endogenous p53 increased MGMT promoter methylation in A549 cells, and transient expression of WT-p53 in p53 null H1299 cells diminished MGMT promoter methylation, whereas the MGMT promoter methylation status was unchanged by expression of L194R-p53. Previous work showed that p53 modulates DNA methyltransferase 1 (DNMT1) expression, were further at was examined chromatin remodeling proteins expression levels of histone deacetyltransferse-1 (HDAC1). We found that p53 knockdown elevated the expression of both DNMT1 and HDAC1 in A549 cells. Conversely, expressing WT-p53 in p53 null H1299 cells reduced DNMT1 and HDAC1 expression. DNMT1 and HDAC1 binding to the MGMT promoter was increased by MGMT promoter methylation and decreased by MGMT promoter demethylation. In summary, E2 and p53 modulated the promoter methylation of ER and MGMT are mediated through a similar molecular mechanism to attenuate their transcription.


目錄
1. 中文摘要 1
2. 英文摘要 3
3. 文獻綜論及序言 6
3.1. 肺癌之流行病學 6
3.2. 抽菸與肺癌 8
3.3. DNA 啟動子甲基化和組織蛋白醯基化參與基因轉錄調控 8
3.4. p53抑癌基因與肺癌 12
3.5. 賀爾蒙與癌症 14
3.6. 雌性素與雌性素受體作用機轉 15
3.7. 雌性素受體甲基化、表現與人類腫瘤之相關性 16
3.8. DNA 修補基因 MGMT 作用機轉 17
3.9. MGMT 基因表現、啟動子甲基化與癌症 20
4. 材料與方法 23
4.1. 材料與藥品 23
4.2. 檢體收集 29
4.3. 細胞培養 29
4.4. 實驗方法 30 4.4.1. Charcoal-dextran 去除胎牛血清中類固醇類激素 30
4.4.2. 以雌性素處理肺癌細胞株 30
4.4.3. 以 5-AZA-dC 處理肺癌細胞 31
4.4.4. 萃取腫瘤與非癌症組織 DNA 31
4.4.5. 肺癌細胞 DNA 之萃取 31
4.4.6. 專一性聚合酶鏈鎖反應偵測基因啟動子之甲基化 32
4.4.7. 肺腫瘤組織 RNA 之萃取 34

4.4.8. 萃取肺癌細胞株 RNA 34 4.4.9. 反轉錄聚合酶連鎖反應 34
4.4.10. 肺癌患者腫瘤組織與非癌症組織雌性素受體之RT-PCR 分析 35
4.4.11. 及時定量聚合酶連鎖反應 35
4.4.12. 萃取肺癌細胞組織蛋白 37
4.4.13. 西方點墨法 37
4.4.14. 核染質免疫沈澱聚合酶連鎖反應 39
4.4.15. DNA定序 41
4.4.16. 膠體 DNA 純化實驗 42
4.4.17. 製備勝任菌體 42
4.4.18. 接合作用 43
4.4.19. 轉形作用 43
4.4.20. 菌落聚合酶鏈鎖反應 43
4.4.21. 萃取質體 DNA 44 4.4.22. 質體製備 44 4.4.23. 細胞轉染實驗 45 4.4.24. 啟動子甲基化定序聚合酶鏈鎖反應 45 4.4.25. 免疫組織化學染色 46
4.5. 統計分析 46
5. 結果 48
5.1. 比較 ER 啟動子甲基化在肺癌與周邊非腫瘤組織之發生頻率
和其mRNA的表現 48
5.2. ER 啟動子甲基化與肺癌臨床因子之相關性 48
5.3. A549 肺癌細胞中 ER 啟動子甲基化在 ER 轉錄活性之影響 49
5.4. 雌性素對 A549 肺癌細胞 ER 啟動子甲基化之影響 49

5.5. ER 啟動子甲基化在肺癌臨床之預後意義 50
5.6. 肺癌患者 MGMT 啟動子甲基化和其 mRNA 表現以及臨床
因子之相關性 51
5.7. 性別、腫瘤型態和 p53 突變等臨床因子對肺癌患者 MGMT
啟動子甲基化之影響 52
5.8. 在肺癌細胞 MGMT 甲基化與 p53 突變的相關性 53
5.9. 雌性素對 MGMT 啟動子去甲基化和其 mRNA 表現之影響 54
5.10. 雌性素引起 MGMT 啟動子去甲基化之可能作用機制 55
5.11. p53 突變對肺癌患者和肺癌細胞之 MGMT 啟動子甲基化
之影響 57
5.12. p53 會參與抑制 MGMT 啟動子之甲基化 57
5.13. p53 抑制 DNMT1 與 HDAC1 表現與 MGMT 啟動子甲
基化之結合活性 59
6. 討論 60
6.1. ER 啟動子甲基化 60
6.2. ER甲基化與肺癌 60
6.3. 雌性素與啟動子甲基化 61
6.4. ER 甲基化與患者之預後 62
6.5. MGMT甲基化 65
6.6. MGMT甲基化與肺癌 65
6.7. MGMT 甲基化與 p53 突變 67
6.8. p53 與 MGMT 轉錄 68
6.9. p53 對 MGMT 甲基化之影響 69
7. 參考文獻 72
8. 表與圖 109
9. 附錄 138

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