Zhang Yongli, Bao Wei, Wang Kai, Lu Wen, Wang Huihui, Tong Huan, Wan Xiaoping
Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Obstetrics and Gynecology, International Peace Maternity & Child Health Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Oncotarget. 2016 Nov 15;7(46):76036-76046. doi: 10.18632/oncotarget.12582.
β-catenin is a key regulatory factor for the Wnt signaling pathway. SOX17 is an important β-catenin inhibitor, while MAML3 is a co-activator of β-catenin-mediated transcription. Out of 120 endometrial cancer (EC) patients, we found that those with tumors expressing higher SOX17 (n=68) had longer recurrence-free survival (P=0.024), while higher MAML3 expression (n=76) was associated with shorter recurrence-free survival (P=0.022). Immunohistochemical and immunoprecipitation analyses revealed that SOX17 and MAML3 co-localized in EC cell nuclei, and the MAML3 C-terminal region was necessary for SOX17 binding. SOX17 regulated MAML3 transcription via binding to the MAML3 promoter, decreasing Wnt pathway protein expression and suppressing EC cell growth and colony formation in vitro. In nude mice, SOX17 over-expression inhibited tumor growth, and co-inhibition or co-overexpression of SOX17 and MAML3 rescued this response. Our results suggest that decreasing SOX17 levels may promote EC development and progression, and that by downregulating MAML3 expression and Wnt signaling, SOX17 acts as a tumor suppressor that may improve outcome in patients with EC.
β-连环蛋白是Wnt信号通路的关键调节因子。SOX17是一种重要的β-连环蛋白抑制剂，而MAML3是β-连环蛋白介导转录的共激活因子。在120例子宫内膜癌（EC）患者中，我们发现肿瘤表达较高SOX17的患者（n = 68）无复发生存期更长（P = 0.024），而较高的MAML3表达（n = 76）与较短的无复发生存期相关（P = 0.022）。免疫组织化学和免疫沉淀分析显示，SOX17和MAML3共定位于EC细胞核中，且MAML3的C末端区域是SOX17结合所必需的。SOX17通过与MAML3启动子结合来调节MAML3转录，降低Wnt通路蛋白表达，并在体外抑制EC细胞生长和集落形成。在裸鼠中，SOX17过表达抑制肿瘤生长，SOX17和MAML3的共同抑制或共同过表达可挽救这种反应。我们的结果表明，降低SOX17水平可能促进EC的发生和进展，并且通过下调MAML3表达和Wnt信号传导，SOX17作为一种肿瘤抑制因子可能改善EC患者的预后。
