TET/miR-26a/EZH2环路调控的表观遗传修饰在胃癌发生发展中的作用

Our recent data demenstrated that miR-26a functions as a tumor suppressor while thhe TET protein family which promote active DNA demethylation as potential oncogenes. Moreover, TETs are the direct targets of miR-26a in GC,and TET1,3 in turn markedly suppresses miR-26a expression. In previous investigation, TET1 contributes to silencing of some genes by facilitating recruitment of PRC2 to CpG-rich gene promoters in mouse ES cells. We also found that TET2 promotes gastric cancer cell transformation in a protein coding-independent. Based on these preliminary results, the role of TETs-mediated DNA demethylation in miR-26a-inhibited GC growth and metastasis will be clarified in this project. We will determine whether TET1,3 regulates miR-26a expression by facilitating recruitment of PRC2 to miR-26a promoters in GC cells. Here we will investigate whether TET2 promotes gastric cancer progression by operating as a competing endogenous RNA (ceRNA) for miR-26a and thus upregulating the expression of miR-26a targets such as TETs and EZH2. In conclusion, our current study is designed to investigate reciprocal regulation and epigentic modulation of TETs, miR-26a and EZH2 in gastric tumorgenesis and progression. It will provide the new evidences to shed light on the mechanisms of gastric carcinogenesis and develop valuable markers of gastric cancer prognosis.

我们发现miR-26a在胃癌中发挥重要的抑瘤功能。TET蛋白家族是重要的去甲基化酶。我们发现TET具有潜在的促癌功能，且受miR-26a靶向调控，TET1,3又可抑制miR-26a表达。文献报道TET1在鼠ES细胞中促进PRC2募集到某些基因启动子导致基因的沉默；此外我们发现TET2可不依赖于蛋白促进胃癌细胞恶性转化。因此本项目我们将研究TET及其介导的DNA去甲化在miR-26a抑制胃癌生长与转移中的作用；证实TET1,3是否通过促进PRC2募集到启动子区而抑制miR-26a表达；阐明TET2是否作为miR-26a ceRNA促进TET自身及EZH2等分子表达调控胃癌发生发展过程。本项目将阐明TET、miR-26a、EZH2相互调控机制及其介导的表观遗传修饰在胃癌发生发展中的作用。该研究成果将为阐明胃癌发病机制提供新的理论依据，并为胃癌患者预后判断提供新的标志物，具有重要的临床应用前景。

研究发现TET家族成员在某些人类肿瘤中发挥抑癌基因作用。然而TET家族的生物学功能及作用模式在胃癌中并不清楚。本项目中我们发现TET1/2/3 RNA水平在胃癌中相比癌旁组织显著上调，并且其上调与肿瘤进展及预后相关。功能研究显示，TET家族促进胃癌恶性转化，并且这种作用是不依赖于其基因CDS，而依赖于其3’UTR 与miR-26相互作用。进一步研究发现，TET家族发挥ceRNA功能，隔离miR-26，诱导EZH2表达，本项目阐明TET家族在胃癌中的新的作用模式，即发挥非编码功能。本项目揭示了TET、miR-26a、EZH2 相互调控机制及其介导的表观遗传修饰在胃癌发生发展中的作用。该研究成果为阐明胃癌发病机制提供新的理论依据，并为胃癌患者预后判断提供新的标志物，具有重要的临床应用前景。