title: Interferon-microRNA signalling drives liver precancerous lesion formation and hepatocarcinogenesis.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
authors: Yingcheng
authors: Y
authors: Yang
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
authors: Ximeng
authors: X
authors: Lin
authors: Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors: Xinyuan
authors: X
authors: Lu
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China National Center for Liver Cancer, Shanghai, China.
authors: Guijuan
authors: G
authors: Luo
authors: Key Laboratory of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Tao
authors: T
authors: Zeng
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China National Center for Liver Cancer, Shanghai, China.
authors: Jing
authors: J
authors: Tang
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
authors: Feng
authors: F
authors: Jiang
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China National Center for Liver Cancer, Shanghai, China.
authors: Liang
authors: L
authors: Li
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China National Center for Liver Cancer, Shanghai, China.
authors: Xiuliang
authors: X
authors: Cui
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
authors: Wentao
authors: W
authors: Huang
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
authors: Guojun
authors: G
authors: Hou
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
authors: Xin
authors: X
authors: Chen
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
authors: Qing
authors: Q
authors: Ouyang
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
authors: Shanhua
authors: S
authors: Tang
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China.
authors: Huanlin
authors: H
authors: Sun
authors: Key Laboratory of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Luonan
authors: L
authors: Chen
authors: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Frank J
authors: FJ
authors: Gonzalez
authors: Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
authors: Mengchao
authors: M
authors: Wu
authors: Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors: Wenming
authors: W
authors: Cong
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China National Center for Liver Cancer, Shanghai, China Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors: Lei
authors: L
authors: Chen
authors: International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China National Center for Liver Cancer, Shanghai, China State Key Laboratory for Oncogenes and Related Genes, Cancer Institute of RenJi Hospital, Shanghai JiaoTong University, Shanghai, China.
authors: Hongyang
authors: H
authors: Wang
mesh_terms: D000107:Acetylation; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism; D008099:Liver / Q000737:chemistry; D008113:Liver Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000032:analysis / Q000235:genetics*; D016328:NF-kappa B / Q000378:metabolism; D041681:NIH 3T3 Cells; D010422:Pentanones; D011230:Precancerous Conditions / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1 / Q000378:metabolism
chemical_list: C498520:Gli1 protein, mouse; C508032:Ifnar1 protein, mouse; D007370:Interferon Type I; C572386:MIRN484 microRNA, human; D035683:MicroRNAs; C573781:Mirn484 microrna, mouse; D016328:NF-kappa B; D010422:Pentanones; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D000071676:Zinc Finger Protein GLI1; D053633:Receptor, Interferon alpha-beta; C027452:diethyl ketone; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: CARCINOGENESIS; HEPATOBILIARY CANCER; INFLAMMATION; INTERFERON; TGF-BETA