TGF-β1 promotes colorectal cancer immune escape by elevating B7-H3 and B7-H4 via the miR-155/miR-143 axis
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Xinru Zhou1,*, Yong Mao2,*, Jianjie Zhu1, Fanyi Meng1, Qi Chen1, Lihua Tao3, Rui Li3, Fengqing Fu4, Cuiping Liu4, Yuanjia Hu5, Weipeng Wang1, Hongjian Zhang1, Dong Hua2, Weichang Chen3, Xueguang Zhang4
1Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
2Department of Oncology, The Fourth Affiliated Hospital of Soochow University, Wuxi, China
3Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
4Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
5Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, China
*These authors contributed equally to this work
Weipeng Wang, email: [email protected]
Keywords: colorectal cancer, tumor evasion, TGF-β1, co-inhibitor, microRNA
Received: May 18, 2016 Accepted: September 02, 2016 Published: September 10, 2016
Transforming growth factor-beta 1 (TGF-β1) suppresses T cell function, promoting tumor immune escape. Yet, whether the depression of TGF-β1 on T cell function is mediated by co-inhibitory molecules B7-H3 and B7-H4 remains largely unclear. Here, we demonstrated that TGF-β1 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-β1 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-β1 leads to T cell-mediated tumor evasion through an increase in B7-H3 and B7-H4 expression.
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