结肠癌低氧条件下TET1 调控HIF-1α 基因及靶基因VEGF 表达的机制研究

Hypoxia environment can affect the level of DNA methylation in colorectal cancer (CRC) and regulate the expression of related genes. DNA methylation levels of HRE sequences in the promoter region regulate Hypoxia-stimulating factor HIF-1α. The high level of DNA methylation inhibits the expression of HIF-1α gene. We focus on whether TET1 is able to adjust DNA methylation of HRE in the promoter region of HIF-1α gene and its target genes under the hypoxic environment, regulate the expression of these genes, and ultimately affect the development of colorectal cancer. We will confirm that whether DNA hydroxymethylation will be influenced under the hypoxic environment and whether this effect will influence the expression of HIF-1α gene. Then we will explore whether TET1 binds to the promoter region of HIF-1α gene, adjust DNA hydroxymethylation level of HRE, and recruit HIF-1α to combine with HRE sequences of its target genes under hypoxic conditions. Finally, we explore whether TET1 is related in proliferation and metastasis of colorectal cancer under hypoxic environment. Based on our preliminary research results, we firstly linked active demethylation with hypoxic stimulation, and administered the main problem in regulation of tumor suppressor gene expression by DNA hydroxymethylation under hypoxic stimulation. Our ultimate goal is to explore the relationship between DNA hydroxymethylation and the development of CRC under hypoxic condition, and to clarify the mechanism of DNA hydroxymethylation inhibition CRC progression.

DNA 羟甲基化通过调节基因启动子区甲基化水平调控基因的表达。低氧刺激因子HIF-1α 通过自身启动子区HRE 序列的DNA 甲基化水平进行自调控，DNA 甲基化水平升高抑制HIF-1α 基因的表达。我们关注低氧环境下DNA 羟甲基化酶TET1能否调节HIF-1α 基因及其靶基因启动子区HRE 序列的DNA 羟甲基化水平，调控此类基因的表达，并最终影响结肠癌的发展。①确定低氧环境下DNA 羟甲基化是否受到影响，并影响HIF-1α 基因的表达。②确定低氧条件下TET1能否结合到HIF-1α 基因启动子区，调节HRE 序列的DNA羟甲基化水平，并确定TET1能否将HIF-1α 蛋白招募到其靶基因HRE 序列上。③确定低氧条件下TET1 能否影响结肠癌的增殖和转移。我们首次围绕DNA羟甲基化在低氧环境下如何调控基因表达为主要问题，阐明低氧条件下DNA 羟甲基化影响结肠癌发展的机制。

低氧环境是肿瘤组织代谢环境的基本特征，低氧刺激已被证实为影响肿瘤演进的重要因素之一。有研究发现，低氧刺激能够影响肿瘤细胞内一些基因启动子区的甲基化水平，这些基因甲基化水平的异常是导致大肠癌（colorectal cancer,CRC）发生和发展的重要表观遗传学修饰。近几年的研究发现，DNA 的羟甲基化（DNA 主动去甲基化）能够调节 DNA 的甲基化水平，并调控肿瘤相关基因的表达。 DNA 羟甲基化通过调节基因启动子区甲基化水平调控基因的表达。确定了低氧条件下DNA羟甲基化通过调节基因启动子区甲基化水平调控基因的表达。低氧条件下DNA羟甲基化水平升高促进HIF-1α和VEGF基因的表达。低氧环境下DNA羟甲基化酶TET1和组蛋白去甲基化酶JMJD1C能够调节HIF-1α基因及其靶基因启动子区HRE序列的DNA羟甲基化水平，调控此类基因的表达，并最终影响结肠癌的发展。①确定低氧环境下DNA羟甲基化受到影响，并影响HIF-1α和VEGF基因的表达。②确定低氧条件下TET1能够结合到HIF-1α和VEGF基因启动子区，调节HRE序列上，并确定JMJD1C能够将TET1蛋白招募到其靶基因HRE序列上。③确定低氧条件下TET1和JMJD1C能影响结肠癌的增殖和转移。我们首次围绕DNA羟甲基化和组蛋白去甲基化在低氧环境下如何调控基因表达为主要问题，阐明低氧条件下表观修饰DNA羟甲基化和组蛋白去甲基化如何交互作用，影响结肠癌发展的机制。