An inflammatory-CCRK circuitry drives mTORC1-dependent metabolic and immunosuppressive reprogramming in obesity-associated hepatocellular carcinoma
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AbstractObesity 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.
All Author(s) ListHanyong 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
Journal nameNature Communications
Detailed descriptionCo-corresponding authors: Grace L.H. Wong, Vincent W.S. Wong and Alfred S.L. Cheng
Volume Number9
PublisherNature Publishing Group
Article number5214
LanguagesEnglish-United Kingdom
Web of Science Subject CategoriesMultidisciplinary Sciences;Science & Technology - Other Topics

Last updated on 2021-18-09 at 23:54