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

• Published in: Nature communications Vol. 9; no. 1; pp. 5214 - 16
• Main Authors: Sun, Hanyong, Yang, Weiqin, Tian, Yuan, Zeng, Xuezhen, Zhou, Jingying, Mok, Myth T. S., Tang, Wenshu, Feng, Yu, Xu, Liangliang, Chan, Anthony W. H., Tong, Joanna H., Cheung, Yue-Sun, Lai, Paul B. S., Wang, Hector K. S., Tsang, Shun-Wa, Chow, King-Lau, Hu, Mengying, Liu, Rihe, Huang, Leaf, Yang, Bing, Yang, Pengyuan, To, Ka-Fai, Sung, Joseph J. Y., Wong, Grace L. H., Wong, Vincent W. S., Cheng, Alfred S. L.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.12.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/109; 13/31; 13/51; 13/89; 13/95; 14/34; 14/63; 38/15; 38/22; 38/44; 38/77; 38/88; 38/90; 631/67/1504/1610/4029; 631/67/2327; 631/67/580; 64/110; 64/60; 692/4020/4021/1607/2751; 692/699/2743/393; Ablation; Androgen receptors; Carbohydrates; Cascades; Cell cycle; Circuits; Gene regulation; Glucose tolerance; Hepatocellular carcinoma; High carbohydrate diet; High fat diet; Humanities and Social Sciences; Inflammation; Insulin; Intolerance; Lipids; Liver; Liver cancer; Metabolism; Mice; multidisciplinary; Nuclear fuels; Obesity; Phosphorylation; Rodents; Science; Science (multidisciplinary); Stat3 protein; Transcription; Transgenic mice; Tumorigenicity
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-07402-8

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. Obesity increases the risk of hepatocellular carcinoma (HCC) especially in men. Here the authors find a potential mechanistic explanation by showing that, in mice, obesity-induced STAT3 cooperates with the androgen receptor to activate the mTORC pathway through up regulation of CCRK, resulting in hepatic steatosis worsening and HCC development via metabolic and immune reprogramming.