Qin Xiaoyu, Wang Xinxin, Liu Feng, Morris Laura E, Wang Xiaowen, Jiang Bin, Zhang Yanjie
Oncology Department, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201900, China.
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
Cancer Lett. 2016 Jun 28;376(1):83-94. doi: 10.1016/j.canlet.2016.03.013. Epub 2016 Mar 11.
Gankyrin is overexpressed in some malignancies. However its roles in colorectal carcinogenesis and underlying mechanisms remain largely unexplored. Here we report that gankyrin promotes the initiation and development of colorectal carcinogenesis by activating mTORC1 signaling through TSC/Rheb dependent mechanism. We further show that Gankyrin overexpression accelerated TSC2 degradation, while knockdown in a panel of colorectal cancer (CRC) cell lines, cell line derived xenografts and CRC patient derived xenograft (PDX) tumors delayed TSC2 degradation, restored the TSC2 protein level, and inhibited mTORC1 signaling and CRC growth. Our findings reveal a unique mechanism by which gankyrin promotes colorectal carcinogenesis and show that gankyrin is a potential therapeutic target to improve the clinical management of CRC.
在某些恶性肿瘤中，甘菊环蛋白过度表达。然而，其在结直肠癌发生过程中的作用及潜在机制在很大程度上仍未被探索。在此我们报告，甘菊环蛋白通过TSC/Rheb依赖机制激活mTORC1信号通路，促进结直肠癌的发生和发展。我们进一步表明，甘菊环蛋白过表达加速了TSC2的降解，而在一组结直肠癌（CRC）细胞系、细胞系来源的异种移植瘤和CRC患者来源的异种移植（PDX）肿瘤中敲低甘菊环蛋白则延迟了TSC2的降解，恢复了TSC2蛋白水平，并抑制了mTORC1信号通路和CRC生长。我们的研究结果揭示了甘菊环蛋白促进结直肠癌发生的独特机制，并表明甘菊环蛋白是改善CRC临床治疗的潜在治疗靶点。
