title: Up-regulation of miR-200b in biliary atresia patients accelerates proliferation and migration of hepatic stallate cells by activating PI3K/Akt signaling.
abstract: An increasing body of evidence suggests that miRNAs are involved in fibrotic process of several organs including heart, lung and kidney. It has been observed recently that aberrant expression of miR-200s are associated with hepatic fibrosis. However, the role and underlying mechanism of miR-200s in hepatic fibrogenesis remains unknown. Here, we investigate the role of miR-200b in the activation of immortalized human hepatic stallate cells (HSCs), LX-2 cells. We firstly found that miR-200b significantly enhanced proliferation and migration of LX-2 cells. Secondly, our findings showed that miR-200b enhanced the phosphorylation of Akt, a downstream effector of phosphatidyl-inositol 3-Kinase (PI3K). FOG2, as the targets of fly miR-8 and human miR-200s, directly binds to p85α and inhibits the activation of the PI3K/Akt pathway. Here, we showed that FOG2 protein levels in LX-2 cells were suppressed significantly by miR-200b mimics. FOG2 knockdown by siRNAs activated the PI3K/Akt signaling, which increased cell growth and migration that mimicked the effect of miR-200b. Conversely, LY294002, a highly selective inhibitor of PI3K, could block phosphorylation of Akt and effect of miR-200b. In addition, we showed that miR-200b enhanced the expression of matrix metalloproteinase-2 (MMP-2), which may increase the migration of LX-2 cells. Finally, our results indicated that the expression of miR-200b was unregulated in the biliary atresia (BA) and associated with liver fibrotic progression. These data suggest a potential mechanism for Akt activation through FOG2 down-regulation by miR-200b that can lead to HSC growth and migration. In view of the putative pathogenic role of miR-200b in HSCs, miR-200b may constitute a potential marker for HSC activation and liver fibrosis progression.
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, 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, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Shanghai Institute of Pediatric Research, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, 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, 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, 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, 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 Key Laboratory of Pediatric Gastroenterology and Nutrition, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
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, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Pan
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, China. Electronic address: caiw1978@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Cai
mesh_terms: D001656:Biliary Atresia / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D002867:Chromones / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D002867:Chromones; D004268:DNA-Binding Proteins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C117427:ZFPM2 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D020778:Matrix Metalloproteinase 2
keywords: Biliary atresia; Hepatic stellate cells; Liver fibrosis; Migration; Proliferation; miR-200b