本文選題：基質金屬蛋白酶　切入點：亞甲基四氫葉酸還原酶　出處：《山東大學》2016年博士論文　論文類型：學位論文

【摘要】：背景宮頸癌是女性生殖道最常見的惡性腫瘤,近年來發(fā)病有年輕化的趨勢。目前認為高危型人乳頭瘤病毒(HPV)的持續(xù)性感染,是引起宮頸癌的基本原因。然而在眾多HPV感染者中,僅有極少數人最終發(fā)展成宮頸癌。人群中HPV的高感染率與宮頸癌實際發(fā)病率之問存在明顯的差異,提示在宮頸癌的發(fā)生過程中,遺傳易感因素起到不容忽視的作用。宮頸癌實際上是外源性感染因素和內源性易感因素共同作用的結果,目前宮頸癌發(fā)病的遺傳易感因素包括基因單核苷酸多態(tài)性(SNPs)已經成為研究的一個方向�；|金屬蛋白酶(MMPs)是一類活性依賴于鋅離子或鈣離子的蛋白水解酶,可降解細胞外基質(ECM),在腫瘤的浸潤、遷移及血管生成等過程中均發(fā)揮著重要作用；目前關于MMPs家族基因多態(tài)性與宮頸癌的相關性研究報道不多。亞甲基四氫葉酸還原酶(MTHFR)是葉酸代謝過程中的關鍵酶,其基因多態(tài)性與多種惡性腫瘤的發(fā)生密切相關。有報道,亞甲基四氫葉酸還原酶MTHFR的基因多態(tài)性與子宮頸癌的發(fā)生相關,然而國內外研究結論并不一致。本研究通過對宮頸癌患者與對照人群中MMPs及MTHFR基因多態(tài)性的對比,探討基質金屬蛋白酶(MMPs)及亞甲基四氫葉酸還原酶(MTHFR)基因多態(tài)性與宮頸癌遺傳易感性及臨床病癌特征的關系。目的采用病例對照研究方法,探討基質金屬蛋白酶MMP2-1306 C/T、 MMP3-11715A/6A、MMP7-181A/G、MMP9-1562C/T以及亞甲基四氫葉酸還原酶MTHFR 677C/T、MTHFR1298A/C基因多態(tài)性與宮頸癌易感性及臨床病理特征的關系,尋找宮頸癌易感因素,為宮頸癌早期診斷、針對性預防提供理論依據。方法研究對象為2012年1月-2016年1月在我院就診的宮頸癌患者,選取同期因其他良性疾病就診者為對照組。病例組及對照組所有入選研究對象均于清晨空腹狀態(tài)取肘靜脈血3ml,置于一次性抗凝管中混勻,入-40℃冰箱內保存,以提取全血基因組DNA。采用聚合酶鏈反應(PCR)和限制性片段長度多態(tài)(RFLP)技術檢測MMP2-1306 C/T、MMP3-11715A/6A、MMP7-181A/G、MMP9-1562C/T、 MTHFR 677C/T、MTHFR1298A/C多態(tài)性位點的基因型。留取宮頸癌(Ⅰ-Ⅱa期)手術治療患者的病理標本,取材后立即放入液氮罐中,轉移至-80℃保存?zhèn)溆?以提取DNA,通過PCR-RFLP技術對多態(tài)性位點的基因型進行檢測。因良性病變切除子宮患者的宮頸標本作為對照。采用SPSS19.0統(tǒng)計軟件對所有數據進行整理分析,計數資料采用卡方檢驗；病例組及對照組基因型頻率分布進行Hardy-weinberg平衡檢驗；Logistic回歸法進行相關性分析。P0.05差異具有統(tǒng)計意義。結果第一部分MMPs及MTHFR基因多態(tài)性與宮頸癌的相關性1、MMP2-1306 C/T、MMP3-11715A/6A、MMP7-181A/G、MMP9-1562C/T、 MTHFR 677C/T和MTHFR1298A/C的基因型頻率分布符合Hardy-Weinberg平衡,研究對象具有代表性。2、MMP2-1306 C/T、MMP7-181A/G及MTHFR 677C/T的基因多態(tài)性與宮頸癌有顯著相關性(p0.05)。3、MMP3-11715A/6A、MMP9-1562C/T及MTHFR1298A/C的基因多態(tài)性與宮頸癌無顯著相關性(p0.05)。第二部分MMPs及MTHFR基因多態(tài)性與宮頸癌臨床病理特征的相關性1、MMP2-1306 C/T、MMP7-181A/G及MTHFR 677C/T的基因多態(tài)性與宮頸癌分期有顯著相關性(p0.05)。2、MMP2-1306 C/T、MMP7-181A/G及MTHFR 677C/T的基因多態(tài)性與宮頸癌患者的淋巴結轉移沒有顯著相關性(p0.05)。3、MMP2-1306 C/T、MMP7-181A/G及MTHFR 677C/T的基因多態(tài)性與宮頸癌的病理組織類型無顯著相關性(p0.05)。4、宮頸癌患者中MTHFR 677C/T的基因多態(tài)分布與MMP2的基因多態(tài)分布具有顯著相關性(p0.05),而與MMP7的基因多態(tài)分布無顯著相關性(p0.05)。結論MTHFR 677C/T、MMP2-1306 C/T和MMP7-181A/G的基因多態(tài)性與宮頸癌的發(fā)生和分期有顯著相關性,臨床可根據患者不同基因型分群進行特異性調整干預方案。
[Abstract]:Background: cervical cancer is the most common female reproductive tract cancer incidence in recent years, the trend of younger. The high-risk human papillomavirus (HPV) persistent infection, is the basic causes of cervical cancer. However, in many HPV infection, only a handful of people eventually develop into cervical cancer. There are obvious differences among the high HPV infection rate and the actual incidence of cervical cancer asked, prompt in the process of cervical carcinogenesis in genetic susceptibility plays a role can not be ignored. Cervical cancer is actually exogenous and endogenous infection factors predisposing factors common result, the heredity of cervical cancer the incidence of predisposing factors including single nucleotide polymorphism (SNPs) has become a research direction. The matrix metalloproteinase (MMPs) is a kind of proteolytic activity is dependent on zinc or calcium ions, degradation of extracellular matrix (ECM), in tumor invasion, migration and angiogenesis plays an important role; there are few reports about the correlation between MMPs gene polymorphism and familial cervical cancer. The methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism, its gene polymorphism and a variety of malignant tumors closely related. There are reports, genetic polymorphisms of methylenetetrahydrofolate reductase MTHFR and the occurrence of cervical cancer, but the findings of research at home and abroad are not consistent. This study of cervical cancer patients with contrast MMPs and MTHFR gene polymorphisms in the crowd, to investigate the expression of matrix metalloproteinase (MMPs) and methylenetetrahydrofolate reductase (MTHFR) the relationship between gene polymorphism and susceptibility to cervical cancer and the clinical features of the disease cancer. Objective to case-control study were to investigate the expression of matrix metalloproteinase MMP2-1306 C/T, MM P3-11715A/6A, MMP7-181A/G, MMP9-1562C/T and methylenetetrahydrofolate reductase MTHFR 677C/T, the relationship between MTHFR1298A/C gene polymorphism and the susceptibility of cervical cancer and the clinical pathological features of cervical cancer, find the predisposing factors for early diagnosis of cervical cancer, targeted prevention and provide a theoretical basis. The research object for the January 2012 -2016 year in January in our hospital in patients with cervical cancer and the same time for other benign disease patients as the control group. The case group and control group all subjects were in the early morning fasting state of umbilical venous blood 3ml, a one-time anti coagulation tube in mixing, into the refrigerator to save -40 C, genomic DNA. extraction by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) detection of MMP2-1306 C/T MMP3-11715A/6A, MMP7-181A/G, MMP9-1562C/T, MTHFR, 677C/T, MTHFR1298A/C genotype polymorphism. Stay The cervical cancer (stage I-II a) pathological specimens of patients with surgical treatment, were immediately placed in liquid nitrogen tank, transferred to the -80 stored at standby, to extract the DNA gene were detected by PCR-RFLP technology on polymorphism. Due to benign lesion of uterine cervical specimens were chosen as control. SPSS19.0 the statistical software analysis of all data, count data using chi square test; case group and control Hardy-weinberg group balance test genotype frequency distribution; correlation analysis.P0.05 the difference has statistical significance of Logistic regression method. The correlation between the first part of the MMPs and MTHFR gene polymorphism and cervical cancer 1, MMP2-1306 C/T, MMP3-11715A/6A. MMP7-181A/G, MMP9-1562C/T, 677C/T and MTHFR genotype frequencies of MTHFR1298A/C with the Hardy-Weinberg equilibrium, the research object is representative of.2, MMP2-1306 C/T, MMP7 There was a significant correlation between -181A/G and MTHFR 677C/T gene polymorphism and cervical cancer (P0.05).3, MMP3-11715A/6A, MMP9-1562C/T and there is no significant correlation between MTHFR1298A/C gene polymorphism and cervical cancer (P0.05). The correlation between the second parts of MMPs and MTHFR gene polymorphism and clinicopathological features of cervical cancer was 1 MMP2-1306, C/T, MMP7-181A/G and MTHFR 677C/T gene polymorphism and cervical cancer staging had significant correlation (P0.05).2, MMP2-1306 C/T, MMP7-181A/G and MTHFR with 677C/T gene polymorphism and cervical cancer lymph node metastasis has no significant correlation (P0.05).3, MMP2-1306 C/T, there is no significant correlation between pathological types of MMP7-181A/G and MTHFR gene polymorphism and cervical cancer (677C/T P0.05).4 gene polymorphism in patients with cervical cancer in MTHFR 677C/T and MMP2 distribution has significant correlation (P0.05), and the distribution and MMP7 gene polymorphism There was no significant correlation (P0.05). Conclusion MTHFR 677C/T, MMP2-1306 C/T and MMP7-181A/G gene polymorphisms are significantly correlated with the occurrence and staging of cervical cancer. According to the different genotypes of patients, clinical intervention can be adjusted.

【學位授予單位】：山東大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R737.33

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