The miR-491-3p/mTORC2/FOXO1 regulatory loop modulates chemo-sensitivity in human tongue cancer

作者：Guopei Zheng, Xiaoting Jia, Cong Peng, Yingen Deng, Jiang Yin, Zhijie Zhang, Nan Li, Min Deng, Xiaorong Liu, Hao Liu, Minying Lu, Chengkun Wang, Yixue Gu, Zhimin He · 发表于：Oncotarget · 年份：2015 · DOI：10.18632/oncotarget.3165 · 被引用次数：49 · 研究领域：Cancer-related molecular mechanisms research、MicroRNA in disease regulation、Circular RNAs in diseases

// Guopei Zheng 1, * , Xiaoting Jia 1, * , Cong Peng 1 , Yingen Deng 1 , Jiang Yin 1 , Zhijie Zhang 1 , Nan Li 1 , Min Deng 1 , Xiaorong Liu 1 , Hao Liu 1 , Minying Lu 1 , Chengkun Wang 1 , Yixue Gu 1 , Zhimin He 1 1 Cancer Hospital and Cancer Research Institute of Guangzhou Medical University, Guangzhou 510095, Guangdong, China * These authors have contributed equally to this work Correspondence to: Zhimin He, e-mail: hezhimin2005@yahoo.com Keywords: tongue cancer, miR-491-3p, Rictor, mTORC2, drug resistance Received: October 17, 2014      Accepted: January 18, 2015      Published: February 19, 2015 ABSTRACT We found that levels of miR-491-3p were decreased in multidrug-resistant tongue cancer (TC) cells. Induction of miR-491-3p expression sensitized TC cells to chemotherapy. In agreement, functional inhibition of miR-491-3p enhanced resistance of TC cells to chemotherapy. We found that miR-491-3p directly targeted mTORC2 component Rictor and inhibited mTORC2 activity, which was increased in resistant TC cells with high p-Akt(Ser473), p-SGK1(Ser422) and p-FOXO1(Thr24) levels. Inhibition of mTORC2 activity via either Rictor knockdown or mTOR inhibitor in turn sensitized TC cells to chemotherapy. In agreement, overexpression of Rictor increased the mTORC2 activity and induced resistance of TC cells to chemotherapy. As a feedback loop, mTORC2 downregulated miR-491-3p expression by inactivating FOXO1, which otherwise would transc...