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Cell cycle-related kinase mediates viral-host signalling to promote hepatitis B virus-associated hepatocarcinogenesis
  1. Zhuo Yu1,2,
  2. Yue-Qiu Gao2,
  3. Hai Feng3,
  4. Ying-Ying Lee4,
  5. May S Li3,
  6. Yuan Tian4,
  7. Minnie Y Y Go4,
  8. Dae-Yeul Yu5,
  9. Yue-Sun Cheung6,
  10. Paul B S Lai1,6,
  11. Jun Yu1,4,7,
  12. Vincent W S Wong1,4,7,
  13. Joseph J Y Sung1,7,
  14. Henry L Y Chan1,4,7,
  15. Alfred S L Cheng3,7
  1. 1Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, P. R. China
  2. 2Department of Liver Disease, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China
  3. 3School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, P. R. China
  4. 4Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, P. R. China
  5. 5Disease Model Research Laboratory, Aging Research Center and World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
  6. 6Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, P. R. China
  7. 7State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, P. R. China
  1. Correspondence to Professor Alfred Sze-Lok Cheng, School of Biomedical Sciences and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR 999077, P. R. China; alfredcheng{at}cuhk.edu.hk and Professor Henry Lik-Yuen Chan, Institute of Digestive Disease, Department of Medicine and Therapeutics and State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR 999077, P. R. China; hlychan@cuhk.edu.hk

Abstract

Background Androgen receptor (AR) signalling contributes to male predominance in hepatocellular carcinoma (HCC), which is more pronounced in HBV-endemic areas. Cell cycle-related kinase (CCRK) is essential for AR-induced hepatocarcinogenesis but its molecular function in HBV-associated HCC remains obscure.

Objective To determine the molecular function of CCRK in HBV-associated HCC.

Design Transcriptional regulation was assessed by chromatin immunoprecipitation, promoter mutation and luciferase reporter assays. Hepatocellular proliferation and tumourigenesis were examined by colony formation, soft agar assays and using HBV X protein (HBx) transgenic mice with low-dose exposure to diethylnitrosamine. Protein expressions were examined in clinical samples and correlated with patient survival by log-rank Mantel–Cox test.

Results Overexpression of CCRK, but not its kinase-defective mutant, activated β-catenin/T cell factor signalling through phosphorylation of glycogen synthase kinase-3β (GSK-3β) at Ser9, led to upregulation of AR transcriptional activity and, subsequently, expression of HBx. The viral transactivator in turn induced CCRK expression through enhanced AR signalling, thus forming a positive regulatory loop. RNA interference silencing of CCRK, which suppressed the CCRK/GSK-3β/β-catenin/AR regulatory loop, significantly suppressed HBx-induced hepatocellular proliferation (p=0.001) and transformation (p<0.001) and remarkably reduced >80% diethylnitrosamine-mediated hepatocarcinogenesis in HBx transgenic mice. Finally, patients with HBV-associated HCC with concordant overexpression of CCRK, GSK-3β phosphorylation at Ser9, active dephosphorylated β-catenin and AR phosphorylation at Ser81 had poorer overall (HR=31.26, p<0.0001) and disease-free (HR=3.60, p<0.01) survival rates.

Conclusions Our findings highlight the critical role of CCRK in a self-reinforcing circuitry that regulates HBV-associated hepatocarcinogenesis. Further characterisation of this intricate viral-host signalling may provide new prognostic biomarkers and therapeutic targets for HCC treatment.

  • Hepatitis B
  • Hepatocellular Carcinoma
  • Gene Regulation
  • Molecular Carcinogenesis
  • Cell Signalling

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