Tumor-secreted miR-214 induces regulatory T cells： a major link between immune evasion and tumor growth  

作　　者：Yuan Yin Xing Cai Xi Chen Hongwei Liang Yujing Zhang Jing Li Zuoyun Wang Xiulan Chen Wen Zhang Seiji Yokoyama Cheng Wang Liang Li Limin Li Dongxia Hou Lei Dong Tao Xu Takachika Hiroi Fuquan Yang Hongbin Ji Junfeng Zhang Ke Zen Chen-Yu Zhang 

机构地区：[1]Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology (JERC-MBB), State Key Laboratory of Pharmaceutical Bioteehnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China [2]State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China [3]Key Laboratory of Protein and Peptide Pharmaceuticals & Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China [4]Department of Allergy and Immunology, The Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan [5]National Laboratory of Biomac-romolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China [6]Wuxi Oncology Institute, the Affiliated Hospital of Jiang Nan University, Wuxi, Jiangsu 214062, China

出　　处：《Cell Research》2014年第10期1164-1180,共17页细胞研究（英文版）

基　　金：We thank ProfAlexander Rudensky （Memorial Sloan-Kettering Cancer Center, New York） for diphtheria toxin-treated Foxp3DrR mice. We thank Drs Zheng-Gang Liu （Cancer Research Institute, NIH） and Dan Wu （Yale University） for their comments on the manuseirpt. This work was supported by grants from the National Basic Research Program of China （973 Program; 2014CB542300）, the National Natural Science Foundation of China （81101330, 31271378 and 81250044）, the Natural Science Foundation of Jiangsu Province （BK2011013 and BK2012014） and the Research Special Fund for Public Welfare Industry of Health （201302018）. This work was also supported by the program for New Century Excellent Talents in University from the Ministry of Education of China （NCET- 12-0261）.

摘　　要：An increased population of CD4＋CD25highFoxp3＋ regulatory T cells （Tregs） in the tumor-associated microenvi- ronment plays an important role in cancer immune evasion. However, the underlying mechanism remains unclear. Here we observed an increased secretion of miR-214 in various types of human cancers and mouse tumor models. Tumor-secreted miR-214 was sufficiently delivered into recipient T cells by microvesicles （MVs）. In targeted mouse peripheral CD4＋ T cells, tumor-derived miR-214 efficiently downregulated phosphatase and tensin homolog （PTEN） and promoted Treg expansion. The miR-214-induced Tregs secreted higher levels of IL-10 and promoted tumor growth in nude mice. Furthermore, in vivo studies indicated that Treg expansion mediated by cancer cell-secreted miR-214 resulted in enhanced immune suppression and tumor implantation/growth in mice. The MV delivery of anti-miR-214 antisense oligonucleotides （ASOs） into mice implanted with tumors blocked Treg expansion and tumor growth. Our study reveals a novel mechanism through which cancer cell actively manipulates immune response via promoting Treg expansion.

关 键 词：secreted microRNA regulatory T cell PTEN MICROVESICLE immune evasion TUMOR 

分 类 号：Q2[生物学—细胞生物学] Q26