CXXC4-AMOTL2-YAP轴在调控胃癌细胞凋亡中的作用及分子机制研究

项目名称： CXXC4-AMOTL2-YAP轴在调控胃癌细胞凋亡中的作用及分子机制研究

项目编号： No.81502386

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 陆海琦

作者单位： 浙江大学

项目金额： 19.5万元

中文摘要： 胃癌等肿瘤中存在Hippo-YAP等信号通路的异常。这些通路的异常既可以是遗传学变化的结果，也可能是表观遗传紊乱导致的相关调控蛋白表达异常。Hippo-YAP信号通路通过调控细胞凋亡等过程与肿瘤发生发展密切相关，但在胃癌中的调控机制尚未明确。我们在前期研究中发现新抑癌基因CXXC4因表观遗传变化在胃癌中表达下调；CXXC4可诱导胃癌细胞凋亡，但具体机制未明；CXXC4可抑制YAP表达及YAP下游靶基因如survivin的转录；CXXC4定位于细胞核，且可能是一个新的转录因子；CXXC4可直接结合YAP负调控因子AMOTL2基因并促进其转录表达。因此，CXXC4可能通过直接调控AMOTL2转录来抑制YAP活性，从而促进细胞凋亡并抑制胃癌发生发展。本项目拟通过分析CXXC4诱导细胞凋亡的机制以及对AMOTL2转录调控的分子机制验证该假说，从而明确胃癌发病机制，为胃癌的临床防治提供新的理论基础。

中文关键词： CXXC4；Hippo-YAP信号通路；AMOTL2；细胞凋亡；胃癌

英文摘要： The dysregulation of many essential signaling pathways is involved in the initiation and progression of human cancers,for instance gastric cancer. These abnormalities can be either attributed to genetic changes or epigenetic disorder-induced aberrant expression of relevant regulatory proteins. Hippo-YAP signaling pathway plays an critical role in the development of human cancers through regulating cell growth,cell proliferation,cell apoptosis and so on,however the regulatory mechanism in gastric cancer remains elusive.In our previous studies,we found that novel tumor suppressor gene CXXC4 was downregulated in gastric cancer cells due to epigenetic changes;CXXC4 can induce gastric cancer cell apoptosis,however the exact mechanism is not yet clear.Moreover,CXXC4 significantly attenuated YAP expression and inhibited the transcription of YAP downstream target genes,such as survivin. Furthermore,we discovered that CXXC4 was located in the nucleus and might be a novel transcription factor;CXXC4 indeed interacted with the negative regulator of Hippo signaling AMOTL2 directly and promoted its expression transcriptionally.Based on these preliminary results,we hypothesized that CXXC4 blunts YAP activity by regulating the transcription of AMOTL2 directly and eventually inhibits gastric cancer development.In summary,we plan to investigate the detailed molecular mechanisms of CXXC4-induced cell apoptosis and transcriptionally regulation of AMOTL2 to verify our hypothesis,which will be beneficial to clarify the pathogenesis of gastric cancer and provide theoretical basis for tumor prevention and treatment.

英文关键词： CXXC4;Hippo-YAP signaling pathway;AMOTL2;cell apoptosis;gastric cancer