An inflammatory-CCRK circuitry drives mTORC1-dependent metabolic and immunosuppressive reprogramming in obesity-associated hepatocellular carcinoma
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摘要Obesity increases the risk of hepatocellular carcinoma (HCC) especially in men, but the molecular mechanism remains obscure. Here, we show that an androgen receptor (AR)-driven oncogene, cell cycle-related kinase (CCRK), collaborates with obesity-induced pro-inflammatory signaling to promote non-alcoholic steatohepatitis (NASH)-related hepatocarcinogenesis. Lentivirus-mediated Ccrk ablation in liver of male mice fed with high-fat high-carbohydrate diet abrogates not only obesity-associated lipid accumulation, glucose intolerance and insulin resistance, but also HCC development. Mechanistically, CCRK fuels a feedforward loop by inducing STAT3-AR promoter co-occupancy and transcriptional up-regulation, which in turn activates mTORC1/4E-BP1/S6K/SREBP1 cascades via GSK3 beta phosphorylation. Moreover, hepatic CCRK induction in transgenic mice stimulates mTORC1-dependent G(-)csf expression to enhance polymorphonuclear myeloid-derived suppressor cell recruitment and tumorigenicity. Finally, the STAT3-AR-CCRK-mTORC1 pathway components are concordantly over-expressed in human NASH-associated HCCs. These findings unveil the dual roles of an inflammatory-CCRK circuitry in driving metabolic and immunosuppressive reprogramming through mTORC1 activation, thereby establishing a pro-tumorigenic microenvironment for HCC development.
著者Hanyong SUN, Weiqin YANG, Yuan TIAN, Xuezhen ZENG, Jingying ZHOU, Myth T.S. MOK, Wenshu TANG, Yu FENG, Liangliang XU, Anthony W.H. CHAN, Joanna H. TONG, Yue-Sun CHEUNG, Paul B.S. LAI, Hector K.S. WANG, Shun-Wa TSANG, King-Lau CHOW, Mengying HU, Rihe LIU, Leaf HUANG, Bing YANG, Pengyuan YANG, Ka-Fai TO, Joseph J.Y. SUNG, Grace L.H. WONG, Vincent W.S. WONG, Alfred S.L. CHENG
期刊名稱Nature Communications
詳細描述Co-corresponding authors: Grace L.H. Wong, Vincent W.S. Wong and Alfred S.L. Cheng
出版年份2018
月份12
日期6
卷號9
出版社Nature Publishing Group
文章號碼5214
國際標準期刊號2041-1723
語言英式英語
Web of Science 學科類別Multidisciplinary Sciences;Science & Technology - Other Topics

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