TMEFF2与lncRNA GAS1在胃癌发生发展中作用及其机制研究

发布时间：2018-05-14 11:16

本文选题：胃癌 + TMEFF2　；参考：《上海交通大学》2015年博士论文

【摘要】：第一部分 TMEFF2在胃癌发生发展中作用及其机制研究基因表达谱芯片显示TMEFF2在胃癌组织中表达降低,然而其在胃癌发生发展中的作用及临床意义未见报道。本研究拟探讨TMEFF2在胃癌发生发展中的作用及临床意义。我们采用基因表达谱芯片及基因富集分析方法探讨TMEFF2基因表达的特征。胃癌细胞AGS和MKN45中转染TMEFF2过表达质粒后分析下游基因的表达变化及对细胞增殖、凋亡等生物学功能的影响。胃正常黏膜上皮细胞GES-1中下调TMEFF2表达后分析对基因组稳定性的影响。质谱分析和免疫共沉淀实验探讨TMEFF2与蛋白酪氨酸激酶SHP-1的相互作用。结果显示TMEFF2在胃癌组织中的表达显著降低,且其表达与胃癌患者的预后相关。GSEA分析显示与细胞增殖、凋亡和DNA损伤相关的基因在TMEFF2低表达组显著富集。TMEFF2过表达后可通过诱导胃癌细胞发生凋亡、周期阻滞而抑制胃癌细胞生长。TMEFF2发挥抑癌基因的功能依赖于TMEFF2与SHP-1的相互结合。TMEFF2与SHP-1在胃癌中的表达存在显著正相关。TMEFF2与SHP-1均高表达的胃癌患者预后较好。第二部分 lncRNA GAS1在胃癌发生发展中作用及其机制研究长非编码RNA(lnc RNA)在肿瘤的发生发展中发挥重要作用,然而胃癌中lnc RNA的研究甚少。本研究通过lnc RNA芯片比较肠型胃癌组织及胃正常黏膜组织lnc RNA的表达差异,筛选出lnc RNA GAS1。从胃正常黏膜到萎缩伴肠化、异型增生及肠型胃癌的发生发展过程中,GAS1的表达逐渐升高。GAS1的表达与肿瘤大小、浸润转移及患者的预后密切相关。体内外实验研究结果显示GAS1可促进胃癌细胞的增殖和浸润转移。GAS1在胃癌中的作用机制研究显示,GAS1可作为“脚手架”结合组蛋白甲基化转移酶WDR5及组蛋白乙酰化转移酶KAT2A到超氧化物歧化酶SOD2的启动子区激活SOD2的转录,进而调控胃癌的生物学行为。机制、功能和临床等多方面的研究均显示GAS1在胃癌发生发展中发挥重要作用,有望成为胃癌防治的新靶点而值得进一步深入研究。
[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.
【学位授予单位】：上海交通大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R735.2

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