An inflammatory-CCRK circuitry drives mTORC1-dependent metabolic and immunosuppressive reprogramming in obesity-associated hepatocellular carcinoma

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 () and Alfred S. L. Cheng ()
Additional contact information
Hanyong Sun: The Chinese University of Hong Kong
Weiqin Yang: The Chinese University of Hong Kong
Yuan Tian: The Chinese University of Hong Kong
Xuezhen Zeng: The Chinese University of Hong Kong
Jingying Zhou: The Chinese University of Hong Kong
Myth T. S. Mok: The Chinese University of Hong Kong
Wenshu Tang: The Chinese University of Hong Kong
Yu Feng: The Chinese University of Hong Kong
Liangliang Xu: The Chinese University of Hong Kong
Anthony W. H. Chan: The Chinese University of Hong Kong
Joanna H. Tong: The Chinese University of Hong Kong
Yue-Sun Cheung: The Chinese University of Hong Kong
Paul B. S. Lai: The Chinese University of Hong Kong
Hector K. S. Wang: The Hong Kong University of Science and Technology
Shun-Wa Tsang: The Hong Kong University of Science and Technology
King-Lau Chow: The Hong Kong University of Science and Technology
Mengying Hu: University of North Carolina at Chapel Hill
Rihe Liu: University of North Carolina at Chapel Hill
Leaf Huang: University of North Carolina at Chapel Hill
Bing Yang: Chinese Academy of Sciences
Pengyuan Yang: Chinese Academy of Sciences
Ka-Fai To: The Chinese University of Hong Kong
Joseph J. Y. Sung: The Chinese University of Hong Kong
Grace L. H. Wong: The Chinese University of Hong Kong
Vincent W. S. Wong: The Chinese University of Hong Kong
Alfred S. L. Cheng: The Chinese University of Hong Kong

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract 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 GSK3β 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.

Date: 2018
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DOI: 10.1038/s41467-018-07402-8

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