本文選題：胃癌 + TMEFF2��； 參考：《上海交通大學(xué)》2015年博士論文

【摘要】：第一部分 TMEFF2在胃癌發(fā)生發(fā)展中作用及其機(jī)制研究基因表達(dá)譜芯片顯示TMEFF2在胃癌組織中表達(dá)降低,然而其在胃癌發(fā)生發(fā)展中的作用及臨床意義未見報(bào)道。本研究擬探討TMEFF2在胃癌發(fā)生發(fā)展中的作用及臨床意義。我們采用基因表達(dá)譜芯片及基因富集分析方法探討TMEFF2基因表達(dá)的特征。胃癌細(xì)胞AGS和MKN45中轉(zhuǎn)染TMEFF2過表達(dá)質(zhì)粒后分析下游基因的表達(dá)變化及對(duì)細(xì)胞增殖、凋亡等生物學(xué)功能的影響。胃正常黏膜上皮細(xì)胞GES-1中下調(diào)TMEFF2表達(dá)后分析對(duì)基因組穩(wěn)定性的影響。質(zhì)譜分析和免疫共沉淀實(shí)驗(yàn)探討TMEFF2與蛋白酪氨酸激酶SHP-1的相互作用。結(jié)果顯示TMEFF2在胃癌組織中的表達(dá)顯著降低,且其表達(dá)與胃癌患者的預(yù)后相關(guān)。GSEA分析顯示與細(xì)胞增殖、凋亡和DNA損傷相關(guān)的基因在TMEFF2低表達(dá)組顯著富集。TMEFF2過表達(dá)后可通過誘導(dǎo)胃癌細(xì)胞發(fā)生凋亡、周期阻滯而抑制胃癌細(xì)胞生長(zhǎng)。TMEFF2發(fā)揮抑癌基因的功能依賴于TMEFF2與SHP-1的相互結(jié)合。TMEFF2與SHP-1在胃癌中的表達(dá)存在顯著正相關(guān)。TMEFF2與SHP-1均高表達(dá)的胃癌患者預(yù)后較好。第二部分 lncRNA GAS1在胃癌發(fā)生發(fā)展中作用及其機(jī)制研究長(zhǎng)非編碼RNA(lnc RNA)在腫瘤的發(fā)生發(fā)展中發(fā)揮重要作用,然而胃癌中l(wèi)nc RNA的研究甚少。本研究通過lnc RNA芯片比較腸型胃癌組織及胃正常黏膜組織lnc RNA的表達(dá)差異,篩選出lnc RNA GAS1。從胃正常黏膜到萎縮伴腸化、異型增生及腸型胃癌的發(fā)生發(fā)展過程中,GAS1的表達(dá)逐漸升高。GAS1的表達(dá)與腫瘤大小、浸潤(rùn)轉(zhuǎn)移及患者的預(yù)后密切相關(guān)。體內(nèi)外實(shí)驗(yàn)研究結(jié)果顯示GAS1可促進(jìn)胃癌細(xì)胞的增殖和浸潤(rùn)轉(zhuǎn)移。GAS1在胃癌中的作用機(jī)制研究顯示,GAS1可作為“腳手架”結(jié)合組蛋白甲基化轉(zhuǎn)移酶WDR5及組蛋白乙�；D(zhuǎn)移酶KAT2A到超氧化物歧化酶SOD2的啟動(dòng)子區(qū)激活SOD2的轉(zhuǎn)錄,進(jìn)而調(diào)控胃癌的生物學(xué)行為。機(jī)制、功能和臨床等多方面的研究均顯示GAS1在胃癌發(fā)生發(fā)展中發(fā)揮重要作用,有望成為胃癌防治的新靶點(diǎn)而值得進(jìn)一步深入研究。
[Abstract]:Part I the role of TMEFF2 in the carcinogenesis and development of gastric cancer and its mechanism; Gene expression microarray showed that the expression of TMEFF2 was decreased in gastric cancer, but its role and clinical significance in the carcinogenesis and development of gastric cancer were not reported. The purpose of this study was to investigate the role and clinical significance of TMEFF2 in the development of gastric cancer. We used gene expression microarray and gene enrichment analysis to study the characteristics of TMEFF2 gene expression. After transfection of TMEFF2 overexpression plasmid into AGS and MKN45 of gastric cancer cells, the changes of downstream gene expression and its effects on cell proliferation, apoptosis and other biological functions were analyzed. Effect of down-regulation of TMEFF2 expression in GES-1 of normal gastric mucosal epithelial cells on genomic stability. The interaction between TMEFF2 and protein tyrosine kinase (SHP-1) was investigated by mass spectrometry and immunoprecipitation. The results showed that the expression of TMEFF2 was significantly decreased in gastric cancer tissues, and its expression was related to the prognosis of gastric cancer patients. Apoptosis and DNA damage related genes can induce apoptosis in gastric cancer cells after overexpression of TMEFF2 in the low expression group of TMEFF2. Cycle arrest inhibits the growth of gastric cancer cells. TMEFF2 plays an important role in the function of tumor suppressor gene. The expression of TMEFF2 and SHP-1 in gastric cancer is positively correlated with the expression of TMEFF2 and SHP-1. The prognosis of gastric cancer patients with high expression of TMEFF2 and SHP-1 is better. The second part: the role and mechanism of lncRNA GAS1 in carcinogenesis and development of gastric cancer; long noncoding RNA(lnc RNAs play an important role in the carcinogenesis and development of gastric cancer. However, there is little research on lnc RNA in gastric cancer. In this study, lnc RNA microarray was used to compare the expression of lnc RNA between gastric carcinoma and normal gastric mucosa, and lnc RNA GAS1 was screened out. The expression of GAS1 increased gradually from normal gastric mucosa to atrophy with intestinal metaplasia, dysplasia and intestinal type gastric cancer. The expression of GAS1 was closely related to tumor size, invasion and metastasis, and prognosis of patients. Experimental results in vitro and in vivo showed that GAS1 could promote proliferation, invasion and metastasis of gastric cancer cells. The mechanism of GAS1 in gastric cancer showed that GAS1 could be used as scaffold binding histone methyltransferase WDR5 and histone acetyltransferase (histone acetyltransferase). The promoter region of superoxide dismutase SOD2 (SOD2) activates the transcription of SOD2 by transferring enzyme KAT2A to the promoter of superoxide dismutase (SOD2). And then regulate the biological behavior of gastric cancer. The mechanism, function and clinical studies show that GAS1 plays an important role in the development of gastric cancer, and it is expected to be a new target for the prevention and treatment of gastric cancer.
【學(xué)位授予單位】：上海交通大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R735.2

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1 孫甜甜;TMEFF2與lncRNA GAS1在胃癌發(fā)生發(fā)展中作用及其機(jī)制研究[D];上海交通大學(xué);2015年

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本文編號(hào)：1887639