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研究生:沈俊安
研究生(外文):Jiyun-An Shen
論文名稱:基質金屬蛋白酶-2,-9,及其組織抑制劑-1,-2基因多形性與泌尿道上皮癌之相關研究
論文名稱(外文):Association study on genetic polymorphisms of matrix melloproteinase-2, -9, tissue inhibitor of metalloproteinase-1, -2 and urothelial carcinoma
指導教授:邱弘毅邱弘毅引用關係
指導教授(外文):Hung-Yi Chiou
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:公共衛生學研究所
學門:醫藥衛生學門
學類:公共衛生學類
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:113
中文關鍵詞:泌尿道上皮癌抽菸喝酒基質金屬蛋白酶
外文關鍵詞:urothelial carcinomamatrix melloproteinaseMMPtissue inhibitor of metalloproteinaseTIMP
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泌尿道上皮癌中以膀胱癌為最常見的癌症,膀胱癌的研究顯示,基質金屬蛋白酶(matrix melloproteinase, MMPs)家族與腫瘤細胞的增生、血管生成及進展有密切的相關,其中又以MMP-2和MMP-9的表現與膀胱癌間最有關係。又MMPs的活性受到基質金屬蛋白酶組織抑制劑(tissue inhibitor of metalloproteinase, TIMPs)的調控。其中TIMP-1及TIMP-2分別會與MMP-9及MMP-2產生特異性的結合,進而抑制其活性。且MMP-2,9、TIMP-1,2的表現亦會受到基因多形性的影響。因此,本研究目的在探討MMP-2,9及TIMP-1,2的基因多形性,是否與罹患泌尿道上皮癌及其臨床病理特徵有關。
本研究為病例對照研究,其中有402位為泌尿道上皮癌膀胱癌、腎盂癌及輸尿管癌患者,及410位經頻率匹配年齡(±2.5歲)及性別之對照組個案。利用結構式問卷收集研究對象之基本人口學及相關危險因子之暴露史,以聚合酶連鎖反應(polymerase chain reaction, PCR)增幅DNA片段,再用限制片段長度多形性(restriction fragment length polymorphism, RFLP)方法進行基因多形性的判定,之後以多變項邏輯式迴歸(multiple logistic regression)進行各危險因子、基因多形性與罹患膀胱癌的多變項分析。
研究結果顯示在調整其它危險因子後,抽菸及喝酒分別有有1.9倍及2.2倍的危險性;MMP-9 C-1562T帶有CC基因型者比其他基因型者有較高的罹患泌尿道上皮癌的危險性OR=1.5(95%CI: 1.1-2.1),而TIMP-2 G-418C基因型為GG者比其他基因型者有較高的罹患泌尿道上皮癌的危險性OR=1.8(95%CI: 1.3-2.5),均達統計上顯著意義。在TIMP-1、MMP-9基因多形性的合併結果顯示,帶有3個以上危險性基因型者,罹患泌尿道上皮癌的危險性達2.3倍(95%CI: 1.1-4.5),達統計顯著水準。合併TIMP-2、MMP-2基因多形性的結果顯示,帶有1個以上危險性基因型者,罹患泌尿道上皮癌的危險性達1.8倍(95%CI: 1.3-2.5),達統計上顯著。在基因與抽菸、喝酒的協同作用中發現,有抽菸、有喝酒且帶有4個以上危險性基因型數目者罹患泌尿道上皮癌的危險性高達12.6倍(95%CI: 3.8-41.3),達統計上顯著。此外,在臨床病理學特徵的分析中,當男性病例組中期別T3-T4與Ta相較下,帶有3個以上危險性基因型者則有3.5倍的危險性(95%CI: 1.2-10.2),達統計上顯著;期別T1-T2與Ta對相較下,帶有3個以上危險性基因型者則有2.5倍的危險性(95%CI: 1.1-5.6),達統計顯著水準;在男性病例組中級別G2與G1相較下,帶有3個以上危險性基因型者則有2.8倍的危險性(95%CI: 1.0-7.5),達統計上顯著。
根據上述的結果認為,泌尿道上皮癌與MMP-9 C-1562T及TIMP-2 G-418C基因多形性之間有顯著相關,且在基因與抽菸、喝酒的協同作用下,罹患泌尿道上皮癌的危險性上升;並且癌細胞分化程度、侵襲程度與TIMP-1,2及MMP-2,9的危險基因型數目愈多有關,因此TIMP-1,2及MMP-2,9也許可作為泌尿道上皮癌及其預後的腫瘤標記。
Background: Urothelial carcinoma (UC) mostly occurs in the bladder and its major risk factor is cigarette smoking. The surrival and recurrence of bladder cancer is dependent on the stage and grade of the initial tumor. For patients who affected with nonmuscle-invasive tumor will have better prognosis than those with muscle-invasive tumor. Matrix melloproteinase(MMPs) plays a critical role for tumor cell proliferation, neovascularization and invasion. Previous studies showed that expression of MMP-2,9 is most significantly association with malignant tumors. However, tissue inhibitor of metalloproteinase(TIMP) inhibits the activity of MMP, that is TIMP-1 binds to inactivate MMP-9, whereas TIMP-2 specifically inhibits MMP-2 activity.Therefore, the specific aim of the study is to investigate the associated between UC and genetic polymorphisms of MMP-2,9 and TIMP-1,2.
Methods: A total of 402 pathologically confirmed UC patients and 410 controls were recruited from Chi Mei Hospital, Chia-yi Christian Hospital and Shin Kong Wu Ho_Su Memorial Hospital. Controls were matched to the cases by age (±2.5 years) and sex. All cases and controls were interviewed during hospital admission by well-trained interviewers using standardized structured questionnaires including demographic variables and other traditional risk factors for UC. Genetic polymorphisms of studied markers were genotyped using a PCR-RFLP assay. Odds ratios (ORs) and 95% confidence interval (CI), obtained from unconditional multiple logistic regression, were used to measure the strength of the association between risk factors and risk of UC.
Results: Cigarette smokers had 1.9-folds risk and alcohol drinkers had 2-folds risk for development of UC after adjustment for age, sex, and educational level. For study subjects who with MMP-9 -1562CC genotype had 1.5-folds risk of UC compared with other genotypes of the marker. When study subjects with TIMP-2 -418GG genotype, we observed a statistically significant increased risk of UC (adjusted OR=1.8, 95%CI: 1.3–2.5). When the combined effects of MMP-9 and TIMP-1 polymorphisms and used MMP-9 -1562CC, MMP-9 279RR+RQ, MMP-9 574PR+PP and TIMP-1 CT+CC as the risk genotypes, a significantly increased risk of UC was associated with the subjects who carried more than four risk genotypes (adjusted OR=2.3, 95% CI: 1.1-4.5). When the combined effects of MMP-2 and TIMP-2 polymorphisms and used MMP-2 -1306CC and TIMP-2 -418GG as the risk genotypes, a significantly increased risk of UC was associated with the subjects who carried more than two risk genotypes (adjusted OR=1.8, 95% CI: 1.3-2.5). The joint effect with gene, cigarette smoking and alcohol drinking was also examined. The results showed that subjects who had cigarette smoking, alcohol drinking and carried more then five risk genotypes of MMP-2,9 and TIMP-1,2 have 12.6-folds risk for development of UC than those who did not have cigarette smoking, alcohol drinking and also carried less than one risk genotype. Moreover, the male subjects carried more than four risk genotypes of MMP-2,9 and TIMP-1,2 have increased risk of T3-T4 initial tumor than those with less than two risk genotypes of MMP-2,9 and TIMP-1,2 (adjusted OR=3.5, 95% CI: 1.2-10.2). The male subjects carried more than four risk genotypes of MMP-2,9 and TIMP-1,2 have 2.5-folds risk of T1-T2 initial tumor than those with less than two risk genotypes of MMP-2,9 and TIMP-1,2 (95% CI: 1.1-5.6). The male subjects carried more than four risk genotypes of MMP-2,9 and TIMP-1,2 have 2.8-folds risk of G2 initial tumor than those with less than two risk genotypes of MMP-2,9 and TIMP-1,2 (95% CI: 1.0-7.5).
Conclusion: In summary, MMP-9 C-1562T and TIMP-2 G-418C polymorphisms were associated with UC risk. The tumor stage and differentiation grade progressed with the increasing numbers of MMP-2,9 and TIMP-1,2 risk genotypes.
表 目 錄 ix
圖 目 錄 i
第一章 前言 1
第二章 文獻探討 2
第一節 泌尿道上皮癌之流行病學研究 2
第二節 泌尿道上皮癌危險因子之流行病學研究 4
第三節 基質金屬蛋白酶(MMPs)及其組織抑制劑(TIMPs) 6
第四節 MMPs的基因多形性 11
第五節 TIMPs的基因多形性 18
第六節 研究目的 21
第七節 研究假設 22
第八節 研究架構 23
第三章 材料與方法 24
第一節 研究對象 24
第二節 危險因子之資料收集 24
第三節 腫瘤的分期與分級 24
第四節 實驗方法 26
第五節 資料處理與統計分析 38
第四章 結果 39
第一節 研究對象之人口背景學資料 39
第二節 泌尿道上皮癌與危險因子之關係 41
第三節 基因多形性與泌尿道上皮癌之相關性 47
第四節 抽菸狀況與基因多形性之交互作用及多變項分析 60
第五節 泌尿道上皮癌個案的分級/分期和基因多形性之關係 70
第六節 綜合危險因子交互作用分析 79
第五章 討論 87
參考文獻 92
附件
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