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Interferon–microRNA signalling drives liver precancerous lesion formation and hepatocarcinogenesis
  1. Yingcheng Yang1,2,
  2. Ximeng Lin1,2,
  3. Xinyuan Lu3,
  4. Guijuan Luo1,4,
  5. Tao Zeng5,
  6. Jing Tang1,4,
  7. Feng Jiang1,
  8. Liang Li1,4,
  9. Xiuliang Cui1,4,
  10. Wentao Huang1,
  11. Guojun Hou1,
  12. Xin Chen1,
  13. Qing Ouyang1,
  14. Shanhua Tang1,
  15. Huanlin Sun1,
  16. Luonan Chen5,
  17. Frank J Gonzalez6,
  18. Mengchao Wu2,
  19. Wenming Cong3,
  20. Lei Chen1,4,6,
  21. Hongyang Wang1,4,7
  1. 1International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
  2. 2Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
  3. 3Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
  4. 4National Center for Liver Cancer, Shanghai, China
  5. 5Key Laboratory of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
  6. 6Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
  7. 7State Key Laboratory for Oncogenes and Related Genes, Cancer Institute of RenJi Hospital, Shanghai JiaoTong University, Shanghai, China
  1. Correspondence to Dr Hongyang Wang, International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China; hywangk{at}vip.sina.comLei Chen, International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China; Chenlei{at}smmu.edu.cn

Abstract

Objective Precancerous lesion, a well-established histopathologically premalignant tissue with the highest risk for tumourigenesis, develops preferentially from activation of DNA damage checkpoint and persistent inflammation. However, little is known about the mechanisms by which precancerous lesions are initiated and their physiological significance.

Design Laser capture microdissection was used to acquire matched normal liver, precancerous lesion and tumour tissues. miR-484−/−, Ifnar1−/− and Tgfbr2△hep mice were employed to determine the critical role of the interferon (IFN)–microRNA pathway in precancerous lesion formation and tumourigenesis. RNA immunoprecipitation (RIP), pull-down and chromatin immunoprecipitation (ChIP) assays were applied to explore the underlying mechanisms.

Results miR-484 is highly expressed in over 88% liver samples clinically. DEN-induced precancerous lesions and hepatocellular carcinoma were dramatically impaired in miR-484−/− mice. Mechanistically, ectopic expression of miR-484 initiates tumourigenesis and cell malignant transformation through synergistic activation of the transforming growth factor-β/Gli and nuclear factor-κB/type I IFN pathways. Specific acetylation of H3K27 is indispensable for basal IFN-induced continuous transcription of miR-484 and cell transformation. Convincingly, formation of precancerous lesions were significantly attenuated in both Tgfbr2△hep and Ifnar1−/− mice.

Conclusions These findings demonstrate a new protumourigenic axis involving type I IFN–microRNA signalling, providing a potential therapeutic strategy to manipulate or reverse liver precancerous lesions and tumourigenesis.

  • CARCINOGENESIS
  • HEPATOBILIARY CANCER
  • INFLAMMATION
  • INTERFERON
  • TGF-BETA

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