Up-regulation of miR-200b in biliary atresia patients accelerates proliferation and migration of hepatic stallate cells by activating PI3K/Akt signaling

Cell Signal. 2014 May;26(5):925-32. doi: 10.1016/j.cellsig.2014.01.003. Epub 2014 Jan 8.


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.

Keywords: Biliary atresia; Hepatic stellate cells; Liver fibrosis; Migration; Proliferation; miR-200b.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biliary Atresia / metabolism
  • Biliary Atresia / pathology
  • Cell Line
  • Cell Movement
  • Cell Proliferation
  • Chromones / pharmacology
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Down-Regulation
  • Hepatic Stellate Cells / cytology
  • Hepatic Stellate Cells / metabolism
  • Humans
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / pathology
  • Matrix Metalloproteinase 2 / metabolism
  • MicroRNAs / metabolism*
  • Morpholines / pharmacology
  • Phosphatidylinositol 3-Kinase / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA, Small Interfering / metabolism
  • Signal Transduction / drug effects
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transforming Growth Factor beta1 / pharmacology
  • Up-Regulation


  • Chromones
  • DNA-Binding Proteins
  • MIRN200 microRNA, human
  • MicroRNAs
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • RNA, Small Interfering
  • Transcription Factors
  • Transforming Growth Factor beta1
  • ZFPM2 protein, human
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt
  • Matrix Metalloproteinase 2