LncRNA AC002454.1近程调控CDK6基因的表达影响胃癌增殖与侵袭的机制研究

项目名称： LncRNA AC002454.1近程调控CDK6基因的表达影响胃癌增殖与侵袭的机制研究

项目编号： No.81502040

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： 李鹰飞

作者单位： 广州医科大学

项目金额： 19万元

中文摘要： 胃癌是一种分子网络疾病，非编码RNA调控异常是其重要节点。我们前期研究发现胃癌lncRNA AC002454.1启动子处于异常低甲基化状态，并导致高表达，但其在胃癌中的生物学功能尚不明确。生物信息学分析发现AC002454.1与其上游邻近的癌基因CDK6可竞争结合mi-33a/b，预实验发现AC002454.1与CDK6在胃癌组织中表达呈正相关，提示AC002454.1可能通过ceRNA活性结合有限的miR-33a/b，减少miR-33a/b对CDK6的抑制作用，近程调控CDK6基因的表达，促进胃癌的增殖侵袭。本项目将阐明AC002454.1甲基化异常→ceRNA→miRNAs→CDK6通路为核心的分子机制，以拓展对胃癌增殖侵袭的分子基础认识。并通过对AC002454.1启动子甲基化与胃癌临床指标的相关性研究，找到一种新的评估胃癌恶性程度的生物标记，为胃癌的早期诊断及预后判断提供新的依据。

中文关键词： 胃癌；长链非编码RNA；周期素依赖性激酶6；微小RNA；竞争性内源性RNA

英文摘要： Gastric cancer is a complex disease with aberrant molecular network. Abnormal regulation of non coding RNAs is a critical point. In the previous study, we found that hypomethylation of the promoter in lncRNA AC002454.1 results in high expression of AC002454.1, but the biological significance is still obscure. Based on the bioinformatics analysis, we found an upstream gene of AC002454.1, CDK6, can cross-talk with AC002454.1 via competing shared for miR-33a/b. Based on our preliminary study, we further found an positive correlation between the expression of CDK6 and AC002454.1 in gastric cancer tissues. These results indicatd that AC002454.1 can function as ceRNA (competing endogenous RNA) to enhance the expression of miR-33a/b target gene CDK6 through competitively sequester miR-33a/b and promotes gastric cancer cell proliferation and invasion. In this study will illustrate a regulatory network involving aberrant methylation of AC002454.1→ceRNA→miRNAs→CDK6. The results may contribute to a better understanding of the molecular basis of gastric cancer development. The study will also investigate the relationship between the methylation status of AC002454.1 promoter and clinical indicators of gastric cancer to find a new evaluation of gastric cancer biomarkers, thus provide a new basis for early diagnosis and prognosis of gastric cancer.

英文关键词： gastric cancer;Long non coding RNA;cyclin-dependent kinase 6;miRNA;competing endogenous RNA