二甲双胍通过调控PSMD10甲基化影响子宫内膜癌发生发展的机制研究

Endometrial cancer is one of the three major malignant tumors in female reproductive system. Metformin, an oral antidiabetic drug, has the potential of anti-tumor effect. However, its role and mechanism in endometrial cancer is not clear. Our previous studies found that metformin could down-regulate the expression of long noncoding RNA H19, leading to increase the activity of SAHH, and then activate DNMT3B, finally increasing DNA methylation. In the pre experiment, we found that the promoter methylation level of PSMD10 in type II endometrial cancer cells was increased by treatment of metformin through a whole genome methylation sequencing. In addition, we also found that DNMT3B involved in the regulation of PSMD10 methylation. Moreover, PSMD10 is high expression as an oncoprotein and is closely related to the development and progression of human cancer. Therefore, we hypothesize that metformin may regulate the methylation of PSMD10 promoter via H19/SAHH/DNMT3B signaling pathway, and then influence the development and progression of endometrial cancer. This project intends to clarify the mechanism of metformin on methylation of PSMD10 promoter and explore the effect of metformin on the expression and function of PSMD10 in endometrial cancer cells. In addition, a nude mice xenograft model will be used to investigate relative function and mechanism of metformin. Thus, this project will be helpful to elucidate the new mechanism of metformin and provide a new target for the treatment of endometrial cancer.

子宫内膜癌是女性生殖系统三大恶性肿瘤之一，危害严重。口服降糖药二甲双胍具有抗肿瘤潜能，但其在子宫内膜癌中的作用及机制尚不清楚。我们前期研究发现二甲双胍能下调长链非编码RNA H19的表达，增加SAHH活性，活化DNMT3B，影响DNA甲基化。预实验中我们通过全基因组甲基化测序，发现二甲双胍作用后，II型子宫内膜癌细胞的PSMD10启动子甲基化水平增高，同时DNMT3B参与调控PSMD10甲基化。PSMD10是癌蛋白，其异常高表达与肿瘤发生发展密切相关。因此我们推测，二甲双胍可能通过H19/SAHH/DNMT3B信号通路调控PSMD10甲基化，进而影响子宫内膜癌的发生发展。本项目拟在子宫内膜癌细胞探讨二甲双胍增加PSMD10启动子甲基化的机制，明确二甲双胍对PSMD10表达和功能的影响，并在裸鼠移植瘤模型验证。本项目的开展有助于阐明二甲双胍抗癌作用的新机制，并为子宫内膜癌治疗提供新的靶点。

子宫内膜癌是女性生殖系统三大恶性肿瘤之一，危害严重。口服降糖药二甲双胍具有抗肿瘤潜能，但其在子宫内膜癌中的作用及机制尚不清楚。我们研究发现二甲双胍能下调长链非编码RNA H19的表达，增加SAHH活性，活化DNMT3B，影响DNA甲基化。二甲双胍作用后，子宫内膜癌细胞的PSMD10启动子甲基化水平增高，同时DNMT3B参与调控PSMD10甲基化。PSMD10是癌蛋白，其异常高表达与肿瘤发生发展密切相关。二甲双胍通过H19/SAHH/DNMT3B信号通路调控PSMD10甲基化，继而降低PSMD10表达，影响AKT和STAT3信号通路，抑制子宫内膜癌细胞的增殖、迁移、侵袭。本项目的开展有助于阐明二甲双胍抗癌作用的新机制，并为子宫内膜癌治疗提供新的靶点。