title: Loss of Dicer1 impairs hepatocyte survival and leads to chronic inflammation and progenitor cell activation.
abstract: OBJECTIVE
  To investigate the continuous hepatic histopathological processes which occur in response to the loss of Dicer1.
  
  
  METHODS
  We generated a hepatocyte-selective Dicer1 knockout mouse and observed the gradual hepatic histopathological changes in the mutant liver. Immunohistochemistry and Western blotting were performed to detect Dicer1 expression. We performed hematoxylin and eosin staining, Periodic acid-Schiff staining, Oil Red O staining, and Masson's trichrome staining to detect histological changes in Dicer1-deficient livers. Ki67 immunohistochemistry, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, and Western blotting were used to determine hepatocyte proliferation and apoptosis. Serum biochemistry, cytokine assays, and flow cytometric analysis were performed to quantity liver necrosis and inflammation. Fibrogenic markers were determined by Western blotting and qPCR. CK19, CD133, and OV6 immunofluorescence were used to observe liver progenitor cells. Immunofluorescence and qPCR were performed to reveal embryonic gene expression. We also performed histological staining and Western blotting to analyze hepatocellular carcinoma (HCC) development.
  
  
  RESULTS
  Dicer1 inactivation resulted in significant architecture disorganization and metabolism disruption in the liver. Dicer1 disruption impaired hepatocyte survival and resulted in profound cell apoptosis and continuous necrosis. In contrast to previous reports, the mutant liver exhibited chronic inflammation and progressive fibrosis, and could not be repopulated by Dicer1-positive cells. In addition, extensive activation of hepatic progenitor cells was observed. Primary HCC was observed as early as 4 mo after birth.
  
  
  CONCLUSIONS
  Hepatic loss of Dicer1 results in complex chronic pathological processes, including hepatocyte death, inflammatory infiltration, chronic fibrosis, compensatory proliferation, progenitor activation, and spontaneous hepatocarcinogenesis.
authors.affiliation: Xu-Feng Lu, Yong-Jie Zhou, Lei Zhang, Hong-Jie Ji, Li Li, Yu-Jun Shi, Hong Bu, Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Lu
authors.affiliation: Xu-Feng Lu, Yong-Jie Zhou, Lei Zhang, Hong-Jie Ji, Li Li, Yu-Jun Shi, Hong Bu, Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.
authors.forename: Yong-Jie
authors.initials: YJ
authors.lastname: Zhou
authors.affiliation: Xu-Feng Lu, Yong-Jie Zhou, Lei Zhang, Hong-Jie Ji, Li Li, Yu-Jun Shi, Hong Bu, Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Xu-Feng Lu, Yong-Jie Zhou, Lei Zhang, Hong-Jie Ji, Li Li, Yu-Jun Shi, Hong Bu, Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.
authors.forename: Hong-Jie
authors.initials: HJ
authors.lastname: Ji
authors.affiliation: Xu-Feng Lu, Yong-Jie Zhou, Lei Zhang, Hong-Jie Ji, Li Li, Yu-Jun Shi, Hong Bu, Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Xu-Feng Lu, Yong-Jie Zhou, Lei Zhang, Hong-Jie Ji, Li Li, Yu-Jun Shi, Hong Bu, Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.
authors.forename: Yu-Jun
authors.initials: YJ
authors.lastname: Shi
authors.affiliation: Xu-Feng Lu, Yong-Jie Zhou, Lei Zhang, Hong-Jie Ji, Li Li, Yu-Jun Shi, Hong Bu, Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Bu
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000097:blood; D053487:DEAD-box RNA Helicases / Q000172:deficiency* / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D006521:Hepatitis, Chronic / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D022781:Hepatocytes / Q000201:enzymology* / Q000473:pathology; D018836:Inflammation Mediators / Q000097:blood; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008103:Liver Cirrhosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D018345:Mice, Knockout; D009336:Necrosis; D010641:Phenotype; D043244:Ribonuclease III / Q000172:deficiency* / Q000235:genetics; D013234:Stem Cells / Q000201:enzymology* / Q000473:pathology; D013997:Time Factors
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
keywords: Dicer1; Hepatocellular carcinoma; Liver fibrosis; Liver inflammation; microRNAs