TGF-β1 promotes colorectal cancer immune escape by elevating B7-H3 and B7-H4<i>via</i>the miR-155/miR-143 axis

Abstract

// Xinru Zhou 1, * , Yong Mao 2, * , Jianjie Zhu 1 , Fanyi Meng 1 , Qi Chen 1 , Lihua Tao 3 , Rui Li 3 , Fengqing Fu 4 , Cuiping Liu 4 , Yuanjia Hu 5 , Weipeng Wang 1 , Hongjian Zhang 1 , Dong Hua 2 , Weichang Chen 3 , Xueguang Zhang 4 1 Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou, China 2 Department of Oncology, The Fourth Affiliated Hospital of Soochow University, Wuxi, China 3 Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China 4 Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China 5 Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, China * These authors contributed equally to this work Correspondence to: Weipeng Wang, email: wangweipeng@suda.edu.cn Keywords: colorectal cancer, tumor evasion, TGF-&beta;1, co-inhibitor, microRNA Received: May 18, 2016&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: September 02, 2016&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: September 10, 2016 ABSTRACT Transforming growth factor-beta 1 (TGF-&beta;1) suppresses T cell function, promoting tumor immune escape. Yet, whether the depression of TGF-&beta;1 on T cell function is mediated by co-inhibitory molecules B7-H3 and B7-H4 remains largely unclear. Here, we demonstrated that TGF-&beta;1 elevated the expression of miR-155 in colorectal cancer cells through SMAD3 and SMAD4. The upregulated miR-155 attenuated miR-143 by inhibiting its direct target, the transcription factor CEBPB. Consequently, the direct target genes of miR-143, B7-H3 and B7-H4, were augmented in the cytoplasm and membrane of tumor cells. Over-expression of B7-H3 and B7-H4 in HCT-116 cells induced T cells to secrete TGF-&beta;1 and the immunosuppressive cytokines IL-2, IL-6, and IL-17. Restoration of miR-143 inhibited the growth of HCT-116 xenograft tumors in mice, and also repressed the expression of B7-H3 and B7-H4 in the tumors. Thus, this study reveals the mechanism by which TGF-&beta;1 leads to T cell-mediated tumor evasion through an increase in B7-H3 and B7-H4 expression.