转录因子YY1调控c-Myc介导的GAGE7B高表达促进胃癌进展的机制研究

Gastric cancer is one of the most common malignancies and one of the most common causes of cancer-related mortality. The progression of gastric cancer should be deeply studied especially at molecular level. GAGE7B was found to be upregulated in gastric cancer and could promote the cancer cells' migration and invasion ability. However, the mechanism of the up-regulation of GAGE7B needs to be deeply explored. In our previous study, the regulation of GAGE7B by transcription factors was investigated. The core promoter of GAGE7B was firstly identified and the transcription factors potentially bind to the core promoter were predicted. The subsequent results showed that transcription factors YY1 and c-Myc could upregulate GAGE7B expression. c-Myc upregulate GAGE7B expression by binding to the promoter of GAGE7B directly, however, GAGE7B promoter could not be bound by YY1. Intriguingly, the promoter of c-Myc harbor the potential binding site of YY1, which indicated that YY1 might regulate GAGE7B expression in a c-Myc depended manner. Importantly, the mechanism of the regulation of GAGE7B by YY1 will be explored deeply in this study. In addition, the regulation of the progression of gastric cancer by YY1 via regulating c-Myc mediated GAGE7B high expression will be investigated. The study will shed new light on the mechanism of the abnormal expression and function of GAGE7B in gastric cancer.

胃癌是最常见的恶性肿瘤之一，其致死率高而治愈率低，对于胃癌进展的分子机制还需要更加深入的研究。我们的前期研究发现GAGE7B在胃癌中高表达并且可促进胃癌细胞转移和增殖，但其异常高表达的分子机制尚不清楚。我们首先确定了GAGE7B的核心启动子，预测并发现转录因子YY1和c-Myc可上调GAGE7B的表达。c-Myc可直接结合GAGE7B启动子并上调GAGE7B表达，但未检测到YY1结合GAGE7B启动子。有趣的是，c-Myc启动子区还存在YY1潜在的结合位点，提示YY1可能通过调控c-Myc进而间接调节GAGE7B表达。胃癌细胞中YY1对GAGE7B表达的调控机制是本项目研究的重要内容之一。后续还将探讨YY通过调控c-Myc介导的GAGE7B高表达对胃癌进展的调控。本项目对深入探讨GAGE7B异常高表达的调控机制，及其通过调控GAGE7B促进胃癌进展的机制有着重要意义。

背景:胃癌目前是全球癌症相关死亡的第三大原因，由于肿瘤转移和复发，胃癌患者的预后较差。因此，进一步探讨胃癌发生发展的机制具有重要意义。我们已经证实GAGE7B在胃癌中高表达并促进胃癌进展，后续又对其它胃癌转移相关基因进行了研究。.研究内容:对伴有淋巴结转移(LNM)和无淋巴结转移(LNM)的胃癌标本进行芯片检测。通过RT-qPCR鉴定差异表达基因。采用免疫组化(IHC)法进一步检测HRCT1蛋白表达。通过体外和体内实验研究HRCT1在肿瘤浸润、转移和增殖中的作用。通过Microarray、RT-qPCR和western blot实验检测HRCT1下游靶基因的表达。采用双荧光素酶实验和western blot方法鉴定靶向HRCT1的miRNAs。.重要结果及关键数据:HRCT1在胃癌中表达上调。HRCT1的高表达与较差的总体生存期(OS)和无瘤生存期(DFS)相关。HRCT1在体外可促进胃癌细胞的迁移、浸润和增殖，在体内可促进肿瘤的转移和生长。值得注意的是，我们的数据表明，HRCT1通过激活ERBB2-MAPK信号通路促进胃癌进展。miR-124-3p至少部分地负调控了HRCT1的表达。.科学意义:HRCT1的高表达预示着胃癌患者的较差生存。HRCT1通过激活ERBB2-MAPK通路促进肿瘤进展。HRCT1受miR-124-3p负向调控，这可能是胃癌的潜在治疗靶点。