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Nat Commun. 2018 Dec 6;9(1):5214. doi: 10.1038/s41467-018-07402-8.

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

Author information

1
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.
2
Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
3
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
4
Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
5
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China.
6
Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China.
7
Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China.
8
Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
9
Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy and Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
10
State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong, China.
11
State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
12
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China. wonglaihung@cuhk.edu.hk.
13
State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China. wonglaihung@cuhk.edu.hk.
14
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China. wongv@cuhk.edu.hk.
15
State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China. wongv@cuhk.edu.hk.
16
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China. alfredcheng@cuhk.edu.hk.
17
State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China. alfredcheng@cuhk.edu.hk.

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.

PMID:
30523261
PMCID:
PMC6283830
DOI:
10.1038/s41467-018-07402-8
[Indexed for MEDLINE]
Free PMC Article

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