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研究生:簡文斌
研究生(外文):Wen-Pin
論文名稱:I. IL-10 在肺癌患者對 HPV 感染之感受性研究II. P53 突變、p53 codon72 和 MDM2 SNP309 基因多形性對早期肺癌患者腫瘤復發與臨床預後之影響研究
論文名稱(外文):I. The role of IL-10 on the susceptibility to HPV infection of lung cancerII. The impacts of p53 mutation status, p53 Pro72 and MDM2 SNP 309 polymorphisms on tumor recurrence and clinical outcome of early-stage lung cancer
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:2009
畢業學年度:97
語文別:中文
論文頁數:163
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第一部份中文摘要
過去本研究室發現台灣不抽煙之女性肺癌患者較男性患者,有較高之 HPV 16 與 18 的感染率,但為何女性肺癌有較高之 HPV 感染率,則需進一步之探討。 Interleukin 10 (IL-10) 為維持 TH1 及 TH2 兩大類細胞激素平衡之重要細胞激素。在動物實驗已證實 IL-10 與病毒持續性感染有關。因此假設 (1) 女性肺癌患者有較男性為高之HPV感染率,可能是女性有較高之IL-10 mRNA表現,(2) HPV感染之台灣女性肺癌可能較沒有感染之女性患者,有較高之 IL-10 mRNA表現。本研究以 real-time PCR 分析 121 位肺癌患者腫瘤組織中 IL-10 mRNA 之表現,結果發現在女性、不抽菸之患者,有較高 IL-10 mRNA 表現 (61.7% vs 37.7%, p = 0.008 for gender; 55.8% vs 34.3%, p = 0.032 for smoking status),且在女性肺癌患者之 IL-10 mRNA 表現與 HPV 感染具有正相關性 (p = 0.022)。為了解為何女性患者較男性患者有較高之 IL-10 轉錄活性?本研究以 luciferase- reporter assay和ChIP之結果顯示, p53 可能是 IL-10 之主要轉錄因子,其次發現雌性素可能會經由 ER 路徑以及組織蛋白之醯基化,而促進 IL-10 之轉錄活性。因此推測女性較男性患者有較高之 IL-10 mRNA 表現,可能與其腫瘤之 p53 突變率較低和體內有較高之雌性素有關。為了解 IL-10 mRNA 表現是否與 HPV 之清除有關?以 real-time PCR 分析 60 位 HPV 有感染肺腫瘤組織之 IL-10 mRNA表現與 HPV DNA 拷貝數,結果發現腫瘤組織中 IL-10 mRNA表現高之患者,有較高之 HPV DNA 拷貝數,兩者間呈正相關性 (p = 0.030),而 HPV 感染之 TL-1、TL-2 肺癌細胞亦有較高之 IL-10 表現。若以 PHA 處理健康者之 PBMC 培養於 TL-1 之condition medium (CM),則發現 T-bet 和 IFNγ 被誘發之表現會顯著降低,但以 IL-10 抗體中和,則又恢復表現。本研究發現 IL-10 mRNA 表現高之 TL-1 細胞,被腫瘤細胞毒殺之阻抗性,顯著高於 IL-10 mRNA 低表現之 TL-4 細胞,若同樣以 IL-10 抗體中和後,此抑制現象亦顯著恢復。顯示 IL-10 除了會抑制 T-bet 和 IFNγ 表現,亦會降低免疫細胞清除病毒之能力。在臨床預後分析結果顯示, IL-10 mRNA 高表現又同時有 HPV 16/18 E6 蛋白表現之女性肺癌患者,較 IL-10 低表現又同時沒有HPV16/18 E6 蛋白之患者,有較差之臨床預後。因此 IL-10 表現高可能會抑制清除 HPV 感染以及毒殺腫瘤細胞之免疫能力,而促進 HPV 引起之腫瘤形成。

第二部分中文摘要:
雖然診斷技術日益改進與抗癌新藥不斷開發,非小細胞肺癌患者之存活率至今仍僅有 15% 左右,顯示建立有效之生物標記,預測早期肺癌患者之腫瘤復發或轉移機率以及其臨床預後,應是提升肺癌臨床治療之重要策略。已知 p53 是決定腫瘤發展、藥物反應、以及腫瘤轉移的主要調控者。因此本研究收集306位肺癌患者,以自動 DNA 定序儀分析肺腫瘤組織中之 p53 基因突變,以 RFLP 方法分析 306 肺癌患者非腫瘤組織中之 MDM2 SNP 309 基因型,並以 real-time PCR 分析其中 198 位可獲得腫瘤 mRNA 患者MDM2 及 GADD45 mRNA 表現作為評估 p53 功能之指標。同時以 RFLP 方法分析 266 位患者 p53 codon 72 基因型,這些資料用來了解肺腫瘤組織中之 p53 轉錄活性及功能,是否可用來評估早期肺癌之腫瘤復發率和臨床預後?結果發現 p53 基因正常合併 MDM2 GG 基因型之患者,MDM2 和 GADD45 mRNA 表現量顯著高於 p53 基因正常合併 MDM2 TT 型患者,顯示 p53 基因正常和 MDM2 GG 基因型之患者具有較佳之 p53 轉錄活性或功能,臨床上亦可觀察到早期肺癌患者 p53 基因正常和 MDM2 TT 基因型 (HR=2.9, p = 0.01) 和 p53 突變之患者 (HR=2.5, p = 0.01) 有較差之臨床預後。在追蹤患者腫瘤復發率時發現,早期肺癌患者 p53 基因正常合併 MDM2 GG 型患者復發率,較 TT/TG 型或 p53 突變患者為低,但因早期患者人數過少,未達到統計上差異 (p = 0.087)。在分析 p53 codon 72 基因型發現, Pro allele 之患者較 Arg/Arg 基因型患者有較高之腫瘤復發率 (25% vs 7.5%, p = 0.022),在 p53 突變合併 Pro allele 較 p53 正常合併 Arg/Arg 之肺癌患者,則同樣有較高腫瘤復發之傾向 (31% vs 10.3%, p = 0.052),在第一期肺癌患者亦可觀察到同樣之趨勢 (36.4% vs 5.9%, p = 0.052)。在臨床預後上,可觀察到 p53 突變合併 Pro allele 之第一期患者,較 p53 基因正常合併 Arg/Arg 之患者有較差之臨床預後 (HR = 2.66, 95% CI, 1.21-5.85, p = 0.02)。因此藉由簡易偵測 p53 相關之三種生物標記,用來評估早期肺癌患者之腫瘤復發和其臨床預後,將有助於建立較好之臨床治療策略。


Part I
Our previous report indicated that HPV16/18 infection prevalence in female lung tumors was significantly higher than in male tumors. However, the different susceptibility to HPV infection between genders remains to be elucidated. IL-10 has been shown to suppress virus clearance to lead virus persistent infection in animal model, and it is conceivable that IL-10 is an important cytokine to regulate the homeostasis between TH1 and TH2 cytokine secretions. We therefore hypothesize that IL-10 mRNA expression level in female lung tumors may be higher than that in male tumors to explain why female has higher susceptibility to HPV infection. Herein, 121 lung tumors were enrolled to examine IL-10 mRNA and HPV DNA copy number by real-time PCR to verify whether IL-10 mRNA level is positively correlated with HPV infection and virus clearance. Our data showed that IL-10 mRNA levels in tumors from female and nonsmokers were higher than those in tumors from male and smokers (61.7% vs 37.7%, p = 0.008 for genders; 55.8% vs 34.3%, p = 0.032 for smoking status), and IL-10 mRNA levels were positively correlated with HPV infection in female tumors (p = 0.022), not in male tumors. Moreover, lung tumors with higher IL-10 mRNA levels had higher HPV DNA copy number than those with lower IL-10 mRNA levels (p = 0.030), suggesting that IL-10 expression may be associated with HPV persistent infection in lung tumors. To verify which molecule(s) could be involved in IL-10 transcriptional regulation, luciferase reporter and ChIP analysis showing that p53 may be an important transcription factor to upregulate IL-10 transcription. Additionally, 17-βestrodiol may synergistically enhance IL-10 transcriptional upregulation by p53 in p53 wild-type lung cancer cells. To elucidate whether lung cancer cells with higher IL-10 expression may be more suppression of TH1 cytokines expressions than those with lower IL-10 expression to modulate the the capability of virus clearance and tumor surveillance, two TH1 biomarkers, T-bet and IFN-γ were examined in PBMC from healthy donor which were cultured in the condition medium of TL-1 cells with higher IL-10 in comparison with those in the condition medium of TL-4 cells with lower IL-10 expression. Our data showed that T-bet and IFN-γ expressions in the condition medium of TL-1 cells were more suppressed than those in the condition medium of TL-4 cells. However, the suppression can be restored by the neutralization of IL-10 antiboy. The cytotoxicity of PBMC to TL-1 cells was significantly lower than that of PBMC to TL-4 cells. We also observed that patients with higher IL-10 mRNA plus HPV16/18 E6-positive expression had poorer prognosis than those with lower IL-10 mRNA plus HPV16/18 E6-negative expression. In summary, high expression of IL-10 may suppress the capability of virus clearance and tumor cell cytotoxicity to promote HPV-associated lung tumorigenesis.

Part II
The 5-year survival rate of non-small cell lung cancer remains around 15%, even though the improvement of the diagnostic techinology and new drug discovery are progress since two-decades. P53 is considered to play a key regulator on tumor progression, tumor recurrence, and chemo-therapeutic response. In the present study, 306 lung tumors and adjacent normal lung tissues were enrolled for p53 mutations and MDM2 309SNP by direct sequencing and PCR-RFLP, respectively. Among these, 266 adjacent normal lung tissues were collected to evaluate p53 codon 72 polymorphisms by PCR-RFLP, and 198 lung tumors were collected to determine MDM2 and GADD45 mRNA expressions by real-time PCR for assessment of p53 transcriptional activity. These data were used to verify whether p53 mutation, p53 codon72 genotypes, and MDM2 SNP309 genotypes and their combinations could be associated with tumor recurrence and prognosis. Our data indicated that patients harbored wild-type p53 combined with MDM2 GG genotype had the highest MDM2 and GADD45 mRNA expression levels among the four combinations, and stage-I patients harbored wild-type p53 combined with MDM2 GG genotype had more favorable prognosis than those with wild-type p53 combined with MDM2 TT genotype and p53 mutations. On the contrast, patients with p53 mutations had worser prognosis than those with wild-type p53. In cohort study, stage-I patients harbored wild-type p53 combined with MDM2 GG genotype had lower tumor recurrence rate compared with those harbored MDM2 TT/TG genotype or p53 mutation, but it did not reach statistically significance because a few case numbers were available (p = 0.087). On the other hand, patients with p53 codon 72 Pro allele had higher tumor recurrence rate than those with Arg/Arg genotype (p = 0.022). In addition, patients harbored p53 mutation combined with Pro allele had a higher trend in tumor recurrence rate compared with those harbored wild-type p53 combined with Arg/Arg genotype (p = 0.052), and a similar trend was also observed in stage-I patients (p = 0.052). In the prognostic significance of p53 codon 72 poymorphism, stage I patients harbored p53 mutation combined with Pro allele had poorer prognosis than those harbored wild-type p53 combined with Arg/Arg genotype (HR=2.66, 95% CI, 1.21-5.85, p = 0.02). Therefore, the information of p53 mutation, p53 codon 72 polymorphisms, and MDM2 SNP309 genotype obtained by simple methods may be feasible to assess the tumor recurrence and the clinical outcome of stage I lung cancer, and helpful to choose a favorable clinical strategy to improve patients’ outcome.


第一部份目錄
1. 中文摘要 2
2. 英文摘要 4
3. 研究背景與動機 6
4. 實驗設計 9
5. 文獻綜論 10
5.1 肺癌之流行病學探討 10
5.2 人類乳突瘤病毒致癌機制與不同癌症間相關性及傳染途徑探討 11
5.2.1 人類乳突瘤病毒與肺癌形成相關性探討 12
5.3 免疫系統與人類乳突瘤病毒感染及其相關癌症之探討 13
5.4 Interleukin 10 (IL-10) 簡介 14
5.4.1 IL-10 在免疫系統、病毒感染及清除所扮演之角色探討 15
5.4.2 IL-10 在腫瘤化之角色探討 16
5.4.3 IL-10 之轉錄調控 16
6. 材料與方法: 18
6.1 肺癌患者檢體之收集 18
6.2 萃取腫瘤組織 DNA 18
6.3 血液中白血球之DNA萃取 18
6.4 肺癌患者肺腫瘤組織及血液中白血球 HPV 16/18 DNA 偵測 19
6.5 肺腫瘤組織中 HPV16 拷貝數 (copy number) 分析 20
6.6 肺癌患者肺腫瘤組織、白血球及肺腫瘤細胞 RNA 之萃取 23
6.7 反轉錄聚合酶連鎖反應 (Reverse transcriptase-RT) 24
6.8 反轉錄聚合酶連鎖反應-聚合酶連鎖反應 (RT-PCR) 與
及時定量聚合酶連鎖反應 (Real-time PCR) 24
6.9 細胞培養 26
6.10 分離週邊血液淋巴球 (PBMC) 27
6.11 TL-1 / TL-4 條件培養液 conditioned medium (C.M.) 製備、
裂殖原 (mitogen) - Phytohemagglutinin-L (PHA) 刺激正常
人周邊血液單核細胞、IL-10 中和反應與 T-bet、IFN-γ 基
因 RT-PCR 分析 28
6.12 TL-1 / TL-4 細胞 PKH-26 染色; TL-1 / TL-4 細胞與周邊
血液單核細胞共同培養之細胞毒殺作用; Annexin V 染色以
及流式細胞儀分析 28
6.13 Charcoal-Dextran 去除胎牛血清中類固醇類激素 30
6.14 以雌性素 / doxorubicin 處理肺癌細胞株 30
6.15 核染質免疫沈澱聚合酶連鎖反應 30
6.16 西方點墨法 32
6.17 膠體 DNA 純化實驗 34
6.18製備勝任菌體 34
6.19接合作用 35
6.20轉形作用 35
6.21 菌落聚合酶鏈鎖反應 35
6.22萃取質體 DNA 35
6.23質體製備 36
6.24細胞轉染實驗 37
6.25 IL-10 啟動子片段構築 37
7. 結果 39
7.1. 肺腫瘤組織 IL-10 mRNA 表現與患者臨床因子間之相關性 39
7.2. 不抽菸女性肺癌患者之HPV感染與IL-10 mRNA表現之相關性 39
7.3. 雌性素活化 ERα 路徑可能參與促進IL-10 之轉錄 40
7.4. p53 參與調控 IL-10 之轉錄 41
7.5. 雌性素協力正常 p53 轉錄活化 IL-10 mRNA 之表現性 42
7.6. 肺腫瘤組織中 HPV16 病毒 DNA拷貝數與IL-10 mRNA
表現量之相關性 42
7.7. TL-1細胞表現之IL-10會抑制周邊血球 TH1 細胞激素之T-bet
轉錄因子和IFN-gamma之表現 43
7.8. HPV 感染之肺癌細胞對淋巴球細胞毒殺力較具有抵抗性 45
8. 討論: 46
8.1. IL-10 對免疫系統之影響以及與 HPV 病毒感染之相關性 46
8.2. 腫瘤免疫微環境與 IL-10 在腫瘤化及肺癌患者預後之影響 49
8.3 性別差異與 IL-10 表現之相關性探討 52
9 參考文獻: 56
10 表與圖: 74
11 附錄: 91













第二部份目錄
1. 中文摘要 94
2. 英文摘要 95
3. 研究動機 96
4. 實驗設計 98
5. 文獻縱論 99
5.1 肺癌病患臨床病理特徵及預後之研究 99
5.2 p53 簡介 100
5.2.1 p53基因突變與肺癌患者臨床病理特徵及預後之相關性 101
5.2.2 p53 codon 72 polymorphism之簡介功能介紹、與 p53
突變之相關性及在致腫瘤化與患者預後之角色探討 102
5.3 MDM2 簡介 103
5.3.1 MDM2 表現與病人預後之相關性探討 104
5.3.2 MDM2 SNP309 基因多型性之簡介、功能介紹及在
致腫瘤化與患者預後之角色探討 105
6 材料與方法: 107
6.1肺癌與非癌症患者檢體之收集 107
6.2萃取腫瘤與非癌症組織 DNA 107
6.3 p53 基因 exon 5-8 序列突變分析 107
6.4自動定序反應的製備 (autosequencer) 108
6.5 p53 codon 72 polymorphism 及 MDM2 SNP 309 polymorphism 分析108
6.5.1 p53 codon 72 polymorphism 分析 108
6.5.2 MDM2 SNP 309 polymorphism 分析 109
6.6肺腫瘤組織 RNA 之萃取 109
6.7反轉錄聚合酶連鎖反應 110
6.8及時定量聚合酶連鎖反應 110
6.9 MDM2 P2 啟動子片段分析 111
6.9.1 pGL-3 載體與不同 MDM2 SNP 309 基因型 P2 啟動子
片段的構築 111
6.9.2細胞過渡性轉染 (trasient transfection) 及 Mithramycin A 處理112
6.9.3 ß-galactosidase reporter gene assay 112
6.10統計分析 112
7 結果: 113
7.1 p53 突變和MDM2 SNP309基因型與患者臨床因子之相關性 113
7.2 MDM2 和GADD45 mRNA 表現與 MDM2 SNP309 基因型
之相關性 113
7.3正常 p53 會協力促進 MDM2 GG 基因型之轉錄活性 114
7.4 “GG 型+正常p53”可做為早期肺癌患者之獨立較佳臨床
預後因子 115
7.5 p53 codon 72 基因型與臨床因子之相關性 116
7.6 p53 Pro72 allele 顯著增強 p53 突變在早期肺癌患者預後之角色 116
8 討論: 118
8.1 p53 與肺癌患者預後之相關性 118
8.2 P53 突變 與 MDM2 SNP 309 基因型間交互作用與肺癌患者
之預後 119
8.3 P53 codon 72 基因型與 p53 突變對肺癌患者預後之影響 122
9 參考文獻: 125
10 表與圖: 138
11. 附錄: 161



Part I 參考文獻
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姚慧婷。2008。血液中 HPV 16 / HPV 58 DNA 和 hTERT mRNA 為台灣肺癌之危險標記。私立中山醫大學醫學分子毒理學研究所碩士論文。
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Azar, K. K., Tani, M., Yasuda, H., Sakai, A., Inoue, M., and Sasagawa, T. Increased secretion patterns of interleukin-10 and tumor necrosis factor-alpha in cervical squamous intraepithelial lesions. Hum Pathol, 35: 1376-1384, 2004.
Beissert, S., Hosoi, J., Grabbe, S., Asahina, A., and Granstein, R. D. IL-10 inhibits tumor antigen presentation by epidermal antigen-presenting cells. J Immunol, 154: 1280-1286, 1995.
Berkman, N., John, M., Roesems, G., Jose, P. J., Barnes, P. J., and Chung, K. F. Inhibition of macrophage inflammatory protein-1 alpha expression by IL-10. Differential sensitivities in human blood monocytes and alveolar macrophages. J Immunol, 155: 4412-4418, 1995.
Bohlmeyer, T., Le, T. N., Shroyer, A. L., Markham, N., and Shroyer, K. R. Detection of human papillomavirus in squamous cell carcinomas of the lung by polymerase chain reaction. Am J Respir Cell Mol Biol, 18: 265-269, 1998.
Brady, M. T., MacDonald, A. J., Rowan, A. G., and Mills, K. H. Hepatitis C virus non-structural protein 4 suppresses Th1 responses by stimulating IL-10 production from monocytes. Eur J Immunol, 33: 3448-3457, 2003.
Brooks, D. G., Trifilo, M. J., Edelmann, K. H., Teyton, L., McGavern, D. B., and Oldstone, M. B. Interleukin-10 determines viral clearance or persistence in vivo. Nat Med, 12: 1301-1309, 2006.
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Part II
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