活性维生素D调控卵巢癌MLH1基因的表观遗传学机制研究

卵巢癌是病死率最高和五年生存率最低的妇科恶性肿瘤。MLH1是DNA错配修复系统的重要成员，我们前期研究发现在卵巢癌中存在MLH1启动子甲基化，其蛋白表达下降，与卵巢癌的发生与耐药有重要关系，但是其表观遗传学调控机制不明。活性维生素1,25(OH)2D3能通过去除组蛋白甲基化及DNA甲基化作用参与到肿瘤相关基因的调节。我们预实验发现不同浓度1,25(OH)2D3对卵巢癌SKOV3细胞生长有抑制作用，并呈时间剂量依赖性。因此我们提出假说1,25(OH)2D3很可能通过组蛋白/DNA去甲基化作用，引起组蛋白H3K27去甲基化，使MLH1重新表达。本课题拟采用人卵巢癌细胞和荷癌裸鼠，利用激光显微切割，激光共聚焦及动物活体成像等先进技术，从体内体外分别探讨活性维生素D对MLH1的精细表观遗传学调控机制，为卵巢癌的发生及耐药提供新的靶点。

Ovarian cancer is one of the gynecologic cancers with the highest fatality rate and minimum 5 years survival rate. Our preceding study found that as an important member of DNA mismatch repair system , MLH1, protein expression was decreased, because of its promoter methylation and it play a key role in the occurrence and drug-resistance in ovarian cancer. However, the epigenetic regulation mechanism remains unclear. Active 1, 25 (OH) 2D3 involved in the regulation of tumor related gene by removal of histone methylation and DNA methylation. Our preliminary experiment found that different concentration of 1, 25 (OH) 2 D3 can inhibit the ovarian cancer SKOV3 cell growth, and in a time-dose dependent. Thus we propose the hypothesis that 1, 25 (OH) 2 D3 modulates the expression of MLH1,though histone methylation or DNA demethylation, eventually ,the level of MLH1 elevated. In this program we use human ovarian cancer cells and carcinoma in nude mice, using laser microdissection , confocal laser and vivo imaging in vivo to explore fine epigenetic mechanism of active vitamin.D regulating MLH1 in vitro and in vivo. We hope we could provide new targets of the occurrence and drug resistance in ovarian cancer.