UHRF2通过维持肿瘤干细胞干性促进肠癌发生发展的作用和机制研究

Colorectal cancer is one kind of malignant tumors which severely threatens human health. Dysregulated intestinal stem cells will develop into cancer stem cells, thereby breaking the homeostasis of intestinal epithelium and then causing intestinal cancers. Thus, deeply investigating the regulation of intestinal cancer stem cells is very meaningful for the therapy of colorectal cancer. As one important member of UHRF protein family, UHRF2 has been found highly expressed in various types of human malignant tumors. However, the biological functions and underlying mechanisms of UHRF2 still remain elusive. In the primary work, we found that in the mouse model of ApcMin/+ spontaneous intestinal tumorigenesis, UHRF2 gene knockout resulted in significant decreases in the size and number of intestinal tumors. Moreover, the loss of UHRF2 markedly inhibited the stemness of intestinal cancer stem cells. The primary mechanistic studies indicated that UHRF2 elevated the protein stability of TCF4, which acts as a critical transcription factor downstream the Wnt signaling pathway. More intriguingly, UHRF2 interacted with TCF4 and mediated the sumolyation of TCF4. On the basis of these results, by combining UHRF2 gene knockout model and several intestinal cancer models, this project will aim to systematically investigate the function and mechanism of UHRF2 in the development and progression of intestinal cancers, thus providing new evidence and strategies for the targeted therapy of colorectal cancer.

结直肠癌是一种严重威胁人类健康的恶性肿瘤。肠干细胞的异常调控会导致肿瘤干细胞的形成，从而破坏肠上皮内环境的稳态并最终诱发肠癌。因此，对肠肿瘤干细胞调控的深入研究对于结直肠癌的治疗具有重要意义。UHRF2是UHRF蛋白家族的重要成员，虽然它被报道在人类多种恶性肿瘤中高表达，但其生物学功能和作用机制尚不明确。在前期工作中，我们发现在ApcMin/+小鼠自发性肠癌模型中，UHRF2基因敲除后肠肿瘤的体积、数量均显著下降，肠肿瘤干细胞干性受到明显抑制。初步的机制研究表明UHRF2能提高Wnt信号通路下游重要转录因子TCF4的蛋白稳定性。更为有趣的是，UHRF2能与TCF4发生直接相互作用并使TCF4发生SUMO化修饰。本项目将在这些研究的基础上，通过UHRF2基因敲除模型和多种肠癌模型的结合，对UHRF2在肠癌发生发展中的作用和机制开展全面系统的研究，从而为结直肠癌的靶向治疗提供新的依据和思路。

结直肠癌是一种严重威胁人类健康的恶性肿瘤。肠干细胞的异常调控会导致肿瘤干细胞的形成，从而破坏肠上皮内环境的稳态并最终诱发肠癌。因此，对肠肿瘤干细胞调控的深入研究对于结直肠癌的治疗具有重要意义。UHRF2是UHRF蛋白家族的重要成员，虽然它被报道在人类多种恶性肿瘤中高表达，但其生物学功能和作用机制尚不明确。本研究首次发现UHRF2在结直肠癌中受Wnt信号调节而高表达，且与肿瘤患者不良预后呈正相关。结果显示在ApcMin/+小鼠自发性肠癌模型中，UHRF2基因敲除后肠肿瘤的体积、数量均显著下降，肠肿瘤干细胞干性受到明显抑制，揭示了UHRF2在肠肿瘤的早期发展中发挥了重要的作用。机制研究表明UHRF2能直接介导Wnt信号通路下游重要转录因子TCF4的SUMO化修饰，从而通过提高TCF4的蛋白稳定性，激活了促进肿瘤生长的Wnt/β-catenin信号通路。综上所述，本课题首次揭示了UHRF2在结直肠癌发生发展中的重要作用，并阐明了其与Wnt/β-catenin信号通路形成正反馈调控的分子机制，从而为结直肠癌的临床诊治提供了新的靶点，也为结直肠癌的靶向治疗提供了新的依据和思路。