表观遗传调控miR-124表达与子宫内膜癌恶性生物学特征的关系及其临床意义

Because of the hypermethylation of its gene promoter, the expression miR-124 is suppressed and functions as a tumor suppressor in a variety of tumor tissues. Our previous study explored the expression of miR-124 in endometrial cancer (EC) tissues. We found that miR-124 was suppressed in EC compared with adjacent normal tissues, and ectopic expression of miR-124 significantly suppressed the malignant phenotype of EC cells through targeting STAT3; Moreover, treated cells with DNA methylation tranferase inhibitor could restore the expression of miR-124 in EC cells. Since STAT3 could induce the DNMT1 expression, we hypothesized that hypermethylation-mediated miR-124 suppression activates a positive feedback loop constructing of STAT3 and DNMT1, which further induced DNA methylation and then inhibited miR-124 expression. In this study, we will investigate the relationship between DNA methylation-mediated miR-124 suppression and clinical characters of EC, and explore the mechanisms of miR-124-mediated tumor suppression; To explore the thereaputic value and side effects of DNA methylation inhibitor in EC. This will provide a theoretical basis and method for endometrial therapy in the future.

基因转录异常与表观遗传调控在子宫内膜癌(EC)发生、发展过程产生着重要的作用。我们前期研究表明：1、miR-124在EC中表达量明显下降；2、miR-124可通过靶向调控STAT3而抑制EC细胞的恶性生物学表型；3、运用甲基化转移酶抑制剂可恢复EC细胞中miR-124的表达。根据STAT3能诱导DNA甲基化转移酶1(DNMT1)表达，我们推测因此而异常增多的DNA甲基化使miR-124表达沉默，通过激活STAT3及DNMT1所介导的正反馈调节通路使DNA甲基化加剧，进一步抑制miR-124的表达。本课题拟探讨DNA甲基化介导的miR-124沉默与EC临床特性的相关性及其临床意义，进一步明确miR-124介导的抑癌机制，检测去甲基化药物在诱导miR-124表达对EC的治疗价值及作用效应；为深入探讨miR-124在EC中的表达调控及作用机制提供研究基础，为EC治疗提供新思路。