本文選題：胃癌　切入點(diǎn)：抑癌基因　出處：《浙江大學(xué)》2016年博士論文

【摘要】：研究背景胃癌的發(fā)病率和死亡率高居全球惡性腫瘤的第4和第3位,為我國(guó)最常見(jiàn)的惡性腫瘤之一。近年來(lái)研究表明,胃癌的發(fā)生發(fā)展是一個(gè)多因素、多階段、多基因異常表達(dá)累積的病變過(guò)程。除經(jīng)典的基因缺失與突變機(jī)制外,表觀遺傳學(xué)的改變?cè)谖赴┑陌l(fā)生發(fā)展過(guò)程中逐漸受到重視,其中基因啟動(dòng)子異常甲基化被認(rèn)為是調(diào)控基因表達(dá)的第三種重要機(jī)制。腫瘤抑癌基因(tumor suppressor gene,TSG)是生物體內(nèi)細(xì)胞增殖、分化和凋亡過(guò)程中的負(fù)性調(diào)節(jié)因子之一。由抑癌基因啟動(dòng)子高甲基化引起的基因失活有助于細(xì)胞的無(wú)限制生長(zhǎng),促進(jìn)腫瘤的形成。因此,對(duì)這方面進(jìn)行研究有助于解釋細(xì)胞增殖、分化和癌變等過(guò)程。抑癌基因異常甲基化常在腫瘤早期被檢測(cè)出來(lái),通過(guò)篩選胃癌相關(guān)的基因甲基化譜,能為腫瘤的早期診斷、治療和預(yù)后提供理論及實(shí)驗(yàn)依據(jù)。研究目的通過(guò)分析胃癌組織中抑癌基因p16、hMLH1和CDH1啟動(dòng)子區(qū)甲基化狀態(tài)及其蛋白表達(dá)水平,明確兩者之間的相關(guān)性;統(tǒng)計(jì)分析這3個(gè)基因啟動(dòng)子區(qū)甲基化狀態(tài)和蛋白表達(dá)水平與臨床病理參數(shù)、預(yù)后參數(shù)之間的關(guān)系,揭示這3個(gè)基因在胃癌發(fā)生發(fā)展中的作用;在胃癌細(xì)胞系和正常胃黏膜上皮細(xì)胞系中過(guò)表達(dá)抑癌基因hMLH1,通過(guò)細(xì)胞功能實(shí)驗(yàn),初步探討hMLH1在胃癌中的抑癌作用機(jī)制。研究方法1、檢測(cè)胃癌組織中p16、hMLH1和CDH1基因啟動(dòng)子區(qū)甲基化及其與臨床病理特征和預(yù)后的關(guān)系隨機(jī)選擇經(jīng)病理確診的120例原發(fā)性胃癌患者,所有患者術(shù)前均未行放療和化療,收集胃癌根治術(shù)后腫瘤組織及其相距5cm的配對(duì)癌旁組織。用QIAampDNA Mini Kit試劑盒提取DNA,繼以亞硫酸氫鹽轉(zhuǎn)化。采用甲基化特異性PCR(methylation-specific PCR,MSP)方法檢測(cè)上述樣本中 p16、hMLH1 和 CDH1 基因啟動(dòng)子CpG島甲基化的狀況,在SPSS 18.0統(tǒng)計(jì)軟件中用卡方檢驗(yàn)或Fisher精確檢驗(yàn)分析每個(gè)基因甲基化程度與臨床病理參數(shù)之間的關(guān)系。探討p16、hMLH1和CDH1基因甲基化狀態(tài)與患者總體生存期的關(guān)系用Kaplan-Meier法。整體比較采用Log-rank檢驗(yàn)并繪制生存曲線。2、檢測(cè)胃癌組織中p16、hMLH1和E-cadherin蛋白表達(dá)水平及其與臨床病理特征和預(yù)后的關(guān)系對(duì)120對(duì)胃癌組織和癌旁組織進(jìn)行常規(guī)蘇木精-伊紅(Hematoxylin-eosin staining,HE)染色和免疫組織化學(xué)(Immunohistochemistry,IHC)染色。所有步驟依據(jù)產(chǎn)品說(shuō)明書進(jìn)行,利用PBS(0.01mol/L,pH7.4)替代I抗作為陰性對(duì)照。免疫組化染色結(jié)果判定:p16和E-cadherin蛋白免疫染色陽(yáng)性信號(hào)定位于細(xì)胞漿,hMLH1蛋白免疫染色陽(yáng)性信號(hào)定位于細(xì)胞核,呈棕黃色顆粒,每個(gè)標(biāo)本觀察2個(gè)有代表性的高倍視野,每個(gè)視野計(jì)數(shù)100個(gè)細(xì)胞,確定陽(yáng)性細(xì)胞數(shù)所占的百分比并取它們的平均值,陽(yáng)性細(xì)胞數(shù)≤20%為陰性(-),陽(yáng)性細(xì)胞數(shù)20%為陽(yáng)性(+)。在SPSS 18.0統(tǒng)計(jì)軟件中用卡方檢驗(yàn)或Fisher精確檢驗(yàn)分析每個(gè)蛋白表達(dá)與臨床病理學(xué)參數(shù)之間的關(guān)系。探討p16、hMLH1和E-cadherin蛋白表達(dá)水平與患者總體生存期的關(guān)系用Kaplan-Meier法。整體比較采用Log-rank檢驗(yàn)并繪制生存曲線。用Spearman相關(guān)性分析探討基因啟動(dòng)子甲基化狀態(tài)與其蛋白表達(dá)之間的關(guān)系。3、胃癌細(xì)胞系和正常胃黏膜細(xì)胞系中hMLH1基因啟動(dòng)子區(qū)甲基化和mRNA表達(dá)水平檢測(cè)體外培養(yǎng)胃癌細(xì)胞系(MKN-74、MKN-45、SGC-7901、HGC-27、MGC-803、BGC-823和AGS)和正常胃黏膜上皮細(xì)胞系GES-1。細(xì)胞接種于含10ml/L胎牛血清(56℃滅活30min)及DMEM/F12培養(yǎng)基中,在37℃、含5%CO2的濕潤(rùn)空氣的恒溫密閉式培養(yǎng)箱中培養(yǎng)。取對(duì)數(shù)生長(zhǎng)期的細(xì)胞數(shù)1×106進(jìn)行細(xì)胞DNA抽提及重亞硫酸氫鹽轉(zhuǎn)化,采用MSP方法檢測(cè)8種細(xì)胞株中hMLH1基因啟動(dòng)子甲基化狀況。用Trizol試劑提取細(xì)胞總RNA,并按RT-PCR試劑盒說(shuō)明書進(jìn)行反轉(zhuǎn)錄合成cDNA;熒光定量PCR擴(kuò)增,分析各細(xì)胞系中hMLH1基因mRNA的相對(duì)表達(dá)水平。獲得啟動(dòng)區(qū)子高甲基化且mRNA表達(dá)水平下降的胃癌細(xì)胞系。4、克隆形成檢測(cè)和Transwell實(shí)驗(yàn)構(gòu)建野生型hMLH1基因慢病毒表達(dá)載體(LV-GFP-MLH1),轉(zhuǎn)染啟動(dòng)區(qū)子高甲基化且mRNA表達(dá)水平下降的胃癌細(xì)胞系A(chǔ)GS,建立穩(wěn)定表達(dá)外源性hMLH1和陰性對(duì)照AGS細(xì)胞株。采用克隆形成實(shí)驗(yàn)檢測(cè)hMLH1過(guò)表達(dá)對(duì)AGS細(xì)胞克隆形成能力的影響;Transwell實(shí)驗(yàn)分析hMLH1過(guò)表達(dá)對(duì)AGS細(xì)胞侵襲能力的影響。研究結(jié)果1、MSP檢測(cè)結(jié)果顯示,120例胃癌組織中p16、hMLH1和CDH1基因啟動(dòng)子區(qū)甲基化陽(yáng)性率分別是 36.67%(44/120)、24.17%(29/120)和 25.00%(30/120);癌旁組織中p16、hMLH1和CDH1基因啟動(dòng)子區(qū)甲基化陽(yáng)性率分別是25.83%(31/120)、8.33%(10/120)和 14.17%(17/120)。hMLH1 和 CDH1 兩個(gè)基因甲基化陽(yáng)性率在胃癌組織與癌旁組織之間的差異均具有統(tǒng)計(jì)學(xué)意義(P0.05)。2、hMLH1基因甲基化狀態(tài)與飲酒(P=0.019)、CA199水平(P0.001)和Borrman分型(P = 0.030)有關(guān),有飲酒史患者其hMLH1甲基化率(40.00%)高于無(wú)飲酒史患者(18.89%);CA19937kU/L的胃癌患者其hMLH1甲基化率(53.57%)高于CA199≤37kU/L的胃癌患者(15.22%);Borrman Ⅰ型和Ⅱ型患者其hMLH1甲基化率(66.67%)高于Ⅲ型和Ⅳ型患者(21.93%)。CDH1基因甲基化狀態(tài)與血清癌胚抗原(CEA)水平有關(guān)(P = 0.003),CEA5μg/L的胃癌患者其CDH1甲基化率(46.43%)高于CEA≤5μg/L的胃癌患者(18.48%)。hMLH1基因啟動(dòng)子甲基化與胃癌患者總體生存相關(guān),是獨(dú)立預(yù)后因子,hMLH1基因高甲基化胃癌患者預(yù)后更差。p16和CDH1基因啟動(dòng)子區(qū)甲基化各自與胃癌患者總體生存期無(wú)關(guān),但在聯(lián)合分析中,攜帶2個(gè)或3個(gè)基因甲基化的患者的總體預(yù)后比攜帶0個(gè)或1個(gè)基因甲基化的患者差(χ~2= 3.901,P = 0.048)3、免疫組化結(jié)果顯示,120例胃癌組織中p16、hMLH1和E-cadherin蛋白表達(dá)陽(yáng)性率分別是:36.67%(44/120)、69.17%(83/120)、68.33%(82/120);癌旁組織中,p16、hMLH1和E-cadherin蛋白表達(dá)陽(yáng)性率分別是:86.67%(104/120)、94.17%(113/120)、92.50%(111/120)。p16,hMLH1 和 E-cadhein 蛋白表達(dá)陽(yáng)性率在胃癌組織與癌旁組織之間的差異均具有統(tǒng)計(jì)學(xué)意義(P0.05)。4、胃癌p16蛋白表達(dá)水平與腫瘤大小有關(guān)(P = 0.030),腫塊直徑6cm患者其p16表達(dá)陽(yáng)性率(44.44%)高于腫塊直徑≥6cm的患者(25.00%)。hMLH1蛋白表達(dá)水平與腫瘤標(biāo)記物CA199(P = 0.041)、腫瘤大小(P = 0.036)有關(guān),CA19937kU/L的胃癌患者其hMLH1蛋白表達(dá)陽(yáng)性率(53.57%)低于CA199≤37kU/L幾的胃癌患者(73.91%);腫塊直徑6cm的患者其hMLH1表達(dá)陽(yáng)性率(76.39%)高于腫塊直徑≥6cm患者(58.33%)。E-cadherin蛋白表達(dá)情況與飲酒(P = 0.041)有關(guān),有飲酒史胃癌患者其E-cadherin表達(dá)陽(yáng)性率(53.33%)低于無(wú)飲酒史患者(73.33%)。p16、hMLH1和E-cadherin蛋白表達(dá)水平與胃癌患者總體生存期無(wú)關(guān)。胃癌組織中hMLH1基因甲基化與其蛋白表達(dá)存在負(fù)相關(guān)性(P=0.005)5、胃癌細(xì)胞系(MKN-74、MKN-45、SGC-7901、HGC-27、MGC-803、BGC-823和AGS)中hMLH1基因啟動(dòng)子均為甲基化,正常胃黏膜上皮細(xì)胞系GES-1中hMLH1為非甲基化。各胃癌細(xì)胞系中hMLH1的mRNA表達(dá)水平均低于正常胃黏膜上皮細(xì)胞系。將加MLH1基因過(guò)表達(dá)病毒感染的AGS細(xì)胞組標(biāo)記為實(shí)驗(yàn)組,加陰性對(duì)照病毒感染的AGS細(xì)胞組標(biāo)記為對(duì)照組�？寺⌒纬蓪�(shí)驗(yàn)顯示,對(duì)照組和實(shí)驗(yàn)組的克隆形成數(shù)分別是180±3個(gè)和169±6個(gè),實(shí)驗(yàn)組的克隆形成數(shù)高于對(duì)照組(P= 0.039)。Transwell實(shí)驗(yàn)結(jié)果顯示,對(duì)照組和實(shí)驗(yàn)組的穿膜細(xì)胞數(shù)分別為135±4.08個(gè)和125±4.18個(gè),實(shí)驗(yàn)組的穿膜細(xì)胞數(shù)高于對(duì)照組(P = 0.048)。結(jié)論胃癌組織中p16、hMLH1和CDH1基因啟動(dòng)子區(qū)異常甲基化是頻發(fā)事件,多個(gè)抑癌基因啟動(dòng)子區(qū)異常甲基化同時(shí)存在可能是胃癌發(fā)生發(fā)展的重要機(jī)制之一。hMLH1和CDH1基因啟動(dòng)子區(qū)甲基化可能是胃癌癌變過(guò)程中的重要分子事件,是胃癌早期診斷的潛在分子標(biāo)志物。hMLH1基因啟動(dòng)子區(qū)甲基化可通過(guò)下調(diào)其基因表達(dá),促進(jìn)胃癌細(xì)胞的克隆形成并增強(qiáng)侵襲能力,從而參與胃癌的發(fā)生發(fā)展。hMLH1啟動(dòng)子甲基化與胃癌患者總生存相關(guān),是胃癌患者預(yù)后的獨(dú)立危險(xiǎn)因素;同時(shí),多個(gè)基因甲基化也與預(yù)后相關(guān),可為胃癌患者的精準(zhǔn)治療和預(yù)后預(yù)測(cè)提供理論依據(jù)。
[Abstract]:Background gastric cancer morbidity and mortality in the world's fourth and third malignant tumors, is one of the most common malignant tumor in China. Recent studies show that the occurrence and development of gastric cancer is a multi factor, multi stage, pathological process of cumulative abnormal expression of multiple genes. In addition to the gene deletion and mutation mechanism. Epigenetic changes, has attracted much attention in the development of gastric cancer, the gene promoter methylation is believed to be the third important mechanisms regulating gene expression of tumor suppressor genes (tumor, suppressor gene, TSG) is a biological cell proliferation, differentiation and apoptosis in negative regulation factor one of the unlimited growth caused by tumor suppressor gene promoter hypermethylation of gene inactivation contributes to cells, promote tumor formation. Therefore, this research helps to explain cell proliferation, Division The process and cancer. Hypermethylation of tumor suppressor gene in tumor early detection, through the screening of gastric cancer related gene methylation profiles, for the early diagnosis of cancer, and provide a theoretical and experimental basis for treatment and prognosis. The purpose of the study through the analysis in gastric cancer tissues by p16, hMLH1 and CDH1 promoter methylation and its protein expression level, correlation between; statistical analysis of the 3 gene promoter methylation status and protein expression and clinicopathological parameters, prognosis parameters, revealed that 3 genes in gastric carcinoma; expression of hMLH1 gene in human gastric cancer cells lines and normal gastric epithelial cell line, through cell function experiments, preliminary study of hMLH1 in gastric carcinoma tumor suppressor mechanism. Methods 1 detecting gastric cancer p16, hMLH1 and CDH1 gene promoter Methylation and clinicopathological characteristics and prognosis between randomly selected 120 patients with pathologically confirmed primary gastric cancer patients, all patients were not receiving preoperative radiotherapy and chemotherapy, radical resection of gastric cancer were collected after tumor tissues and paired tumor adjacent tissues. 5cm were extracted by DNA QIAampDNA Mini Kit kit, followed by bisulfite conversion. Methylation specific PCR (methylation-specific PCR MSP) method to detect the samples of p16, hMLH1 and CDH1 gene promoter CpG island methylation status, exact test to analyze the relationship between each gene methylation and clinicopathological parameters by using the chi square test or Fisher in the SPSS 18 statistical software in the study. P16, Kaplan-Meier by using the method of the relationship between hMLH1 and CDH1 gene methylation status and overall survival in patients. The Log-rank test was used to compare and draw survival curves of.2, detection of P in gastric cancer tissues 16, the expression level of hMLH1 and E-cadherin protein and its relationship with clinicopathological features and prognosis of hematoxylin and 120 pairs of gastric carcinoma and eosin (Hematoxylin-eosin staining, HE) staining and immunohistochemical staining (Immunohistochemistry, IHC). All of the steps according to the product specification, the use of PBS (0.01mol/L, pH7.4) replace I as the negative control. Immunohistochemical staining results: p16 and E-cadherin immunostaining positive signal located in the cytoplasm, hMLH1 immunostaining positive signal located in the cell nucleus, brownish yellow granules, each specimen has 2 HPF representative, each field count of 100 cells, identified the percentage of positive cells accounted for and take their average value, the number of positive cells less than 20% as negative (-), the number of positive cells was positive (+ 20%). Using the chi square statistical software in SPSS 18 Test or Fisher exact test analysis of each protein expression of relationship between parameters and clinical pathological study. P16, Kaplan-Meier by using the method of the relationship between hMLH1 and E-cadherin protein expression level and overall survival in patients. The Log-rank test was used to compare the survival curve was drawn. Analysis of the relationship between.3 gene expression and its promoter of protein by the correlation between Spearman, hMLH1 of gastric cancer cell lines and normal gastric mucosa cell line gene promoter methylation and expression of mRNA in gastric cancer cell lines cultured in vitro (MKN-74, MKN-45, SGC-7901, HGC-27, MGC-803, BGC-823 and AGS) and normal gastric epithelial cell line GES-1. cells were cultured in 10ml/L containing fetal bovine serum (56 C inactivation of 30min) and DMEM/F12 medium at 37 degrees C, 5%CO2 medium containing moist air sealed thermostatic incubator. The number of cells in logarithmic growth phase into 1 * 106 The cell extract DNA and bisulfite conversion, using MSP method to detect 8 kinds of cell line hMLH1 gene promoter methylation status. Total cellular RNA was extracted with Trizol reagent, and cDNA was synthesized by reverse transcription by RT-PCR kit; fluorescence quantitative PCR amplification, hMLH1 analysis of various cell lines relative gene mRNA the expression level of the promoter region. To obtain high methylation and low expression of mRNA in gastric cancer cell line.4, and Transwell assay to construct wild-type hMLH1 gene lentiviral vector cloning (LV-GFP-MLH1), transfection of promoter region of high methylation and low expression of mRNA in gastric cancer cell line AGS, and establish a stable expression of exogenous hMLH1 and the negative control cell line AGS. The clone forming test effect of hMLH1 overexpression on AGS cell colony formation; Transwell experimental analysis of hMLH1 over expression on invasion ability of AGS cells. Ring. Results: 1, MSP test results showed that in 120 cases of gastric cancer, p16, hMLH1 and CDH1 gene promoter methylation positive rate was 36.67% (44/120), 24.17% (29/120) and 25% (30/120); p16 in the cancer tissues, hMLH1 and CDH1 gene promoter methylation positive rate were 25.83% (31/120), 8.33% (10/120) and 14.17% (17/120) between.HMLH1 and CDH1 two gene methylation positive rate in gastric cancer tissue and paracancerous tissue were statistically significant (P0.05.2), the methylation status of hMLH1 gene and alcohol (P=0.019), CA199 (P0.001) and Borrman type (P = 0.030), drinking in patients with a history of hMLH1 methylation rate (40%) higher than that of non drinking history patients (18.89%); CA19937kU/L in gastric cancer patients with hMLH1 methylation rate (53.57%) higher than that of CA199 = 37kU/L in patients with gastric cancer (15.22%); Borrman type patients with hMLH1 methylation rate (66.67% ) higher than that of type III and type IV patients (21.93%) the methylation status of.CDH1 gene and serum carcinoembryonic antigen (CEA) level (P = 0.003), CEA5 g/L in gastric cancer patients with CDH1 methylation rate (46.43%) higher than that of CEA is less than or equal to 5 g/L (18.48%.HMLH1) in patients with gastric cancer related gene promoter Zi Jiaji the overall survival of patients with gastric cancer, is an independent prognostic factor of hMLH1 hypermethylation and worse prognosis of patients with gastric cancer.P16 CDH1 gene promoter methylation has nothing to do with their survival in gastric cancer patients in general, but in the joint analysis, the overall prognosis with 2 or 3 gene methylation in patients compared with 0 or 1 gene methylation in patients with poor (~2= 3.901, P = 0.048) 3, immunohistochemistry showed that in 120 cases of gastric cancer, p16, hMLH1 and E-cadherin protein expression positive rate respectively is: 36.67% (44/120), 69.17% (83/120), 68.33% (82/120); tumor tissues, p16 hMLH1, and E-cadheri The positive rate of N expression were 86.67% (104/120), 94.17% (113/120), 92.50% (111/120).P16, were statistically significant difference between the positive rate in gastric cancer tissue and tumor expression of hMLH1 and E-cadhein protein (P0.05).4, the expression level of p16 protein in gastric cancer is related to tumor size (P = 0.030) the diameter of tumor patients with 6cm, the positive rate of p16 (44.44%) is higher than the diameter of tumor was 6cm patients (25%) the expression level of.HMLH1 protein and tumor marker CA199 (P = 0.041), tumor size (P = 0.036), CA19937kU/L of gastric cancer patients the positive rate of hMLH1 expression (53.57%) is lower than CA199 or 37kU/L a few of the patients with gastric cancer (73.91%); the diameter of tumor patients with 6cm the positive expression rate of hMLH1 (76.39%) is higher than the diameter of the tumor more than 6cm patients (58.33%) the expression of.E-cadherin protein and alcohol (P = 0.041), a history of alcohol in gastric cancer patients with E-cadherin positive expression The rate of (53.33%) is lower than that of the non drinking history (73.33%) patients with.P16, hMLH1 and E-cadherin protein expression in patients with gastric cancer overall survival. Negative correlation between the expression of hMLH1 gene methylation and protein in gastric cancer tissues (P=0.005 5), gastric cancer cell lines (MKN-74, MKN-45, SGC-7901, HGC-27, MGC-803, BGC-823 and AGS) in the hMLH1 gene promoter was methylated hMLH1, normal gastric epithelial cell line GES-1 was unmethylated. The expression levels of hMLH1 in the gastric cancer cell line mRNA was lower than that of normal gastric epithelial cell line. The overexpression of MLH1 gene in AGS cell marker virus infection group as experimental group, and negative control AGS cells were labeled virus infection as the control group. The clone formation assay showed that the cloned control group and experimental group which were 180 + 3 and 169 + 6, the experimental group formed the number of clones was higher than the control group (P= 0.039).Transwell. The experiment results show that the number of transmembrane cells were the control group and the experimental group was 135 + 4.08 and 125 + 4.18, the number of transmembrane cells in the experimental group than in the control group (P = 0.048). Conclusion p16 in gastric cancer tissues, hMLH1 and CDH1 gene promoter methylation is a frequent event, multiple tumor suppressor gene promoter hypermethylation at the same time there may be an important mechanism of occurrence and development of gastric carcinoma.HMLH1 and CDH1 gene promoter methylation may be an important molecular event in gastric carcinogenesis, is a potential molecular marker in early diagnosis of gastric cancer by down regulating the gene expression of promoter methylation of.HMLH1 gene, promote the gastric cancer cell formation and enhance the invasion ability, and thus participate in the development of gastric cancer. The methylation of the.HMLH1 promoter associated with the overall survival of patients with gastric cancer were independent risk factors for the prognosis of gastric cancer patients; at the same time, multiple gene methylation The prognosis is also related to prognosis, which can provide a theoretical basis for accurate treatment and prognosis prediction of gastric cancer patients.

【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R735.2

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