title: Dysregulated miR-124 and miR-200 expression contribute to cholangiocyte proliferation in the cholestatic liver by targeting IL-6/STAT3 signalling.
abstract: OBJECTIVE
  Cholestatic liver disease is associated with dysregulated expression of microRNAs (miRNAs). However, it remains unknown whether miRNAs are involved in the cholestasis-induced proliferation of cholangiocytes. In this study, we tested the hypothesis that miRNAs modulate cholangiocyte proliferation through effects on the IL-6 pathway, a known regulator of cholangiocyte proliferation.
  
  
  METHODS
  Expression of IL-6, Foxa2, and phosphorylated signal transducer activator of transcription 3 (STAT3) was investigated in patients with biliary atresia (BA) and in rats subjected to bile duct ligation (BDL). miRNA expression was determined in BA patients and BDL rats, with miRNA array and quantitative real-time PCR. Biological functions of miRNAs were studied using immunoblot, immunohistochemical and proliferation assays. Luciferase reporter assays and Western blots were performed to identify miRNA targets.
  
  
  RESULTS
  Hepatic interleukin-6 (IL-6) expression was significantly elevated in BA patients and BDL rats, while the expression of miR-124 was dramatically decreased in comparison to controls. Moreover, mRNA levels of STAT3 and IL-6 receptor (IL-6R) were inversely correlated with those of miR-124. Ectopic expression of miR-124 inhibited IL-6-mediated cholangiocyte proliferation in vitro and cholangiocyte hyperplasia in vivo, through a mechanism involving direct targeting of the 3'-untranslated region of STAT3 and IL-6R. We further demonstrated that miR-200 family members were significantly upregulated in cholestasis and inhibited FOXA2 expression in cholangiocytes, which further enhanced the expression of IL-6.
  
  
  CONCLUSIONS
  Our findings suggest that downregulation of miR-124 and upregulation of miR-200 collaboratively promote bile duct proliferation through the IL-6/STAT3 pathway.
authors.affiliation: Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Institute of Pediatric Research, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
authors.forename: Yongtao
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
authors.forename: Weihui
authors.initials: W
authors.lastname: Yan
authors.affiliation: Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Shanghai Institute of Pediatric Research, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
authors.forename: Yingwei
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Shanghai Institute of Pediatric Research, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
authors.forename: Kejun
authors.initials: K
authors.lastname: Zhou
authors.affiliation: Shanghai Institute of Pediatric Research, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wen
authors.affiliation: Shanghai Institute of Pediatric Research, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Institute of Pediatric Research, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China. Electronic address: caiw1978@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Cai
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000378:metabolism / Q000473:pathology; D001656:Biliary Atresia / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D002675:Child, Preschool; D002779:Cholestasis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D005260:Female; D051542:Hepatocyte Nuclear Factor 3-beta; D006801:Humans; D007223:Infant; D015850:Interleukin-6 / Q000235:genetics*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013223:Statistics as Topic
chemical_list: C496502:FOXA2 protein, human; D015850:Interleukin-6; C509207:MIRN124 microRNA, human; C548144:MIRN124 microRNA, rat; C533896:MIRN200 microRNA, human; C555600:MIRN200 microRNA, rat; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; D051542:Hepatocyte Nuclear Factor 3-beta
keywords: Cholangiocytes; Cholestasis; IL-6; MicroRNA; Proliferation; STAT3