miR-222 overexpression may contribute to liver fibrosis in biliary atresia by targeting PPP2R2A

J Pediatr Gastroenterol Nutr. 2015 Jan;60(1):84-90. doi: 10.1097/MPG.0000000000000573.


Objective: Biliary atresia (BA) is a devastating liver disease in infants. Progressive hepatic fibrosis is often observed in postoperative patients with BA even after a successful Kasai portoenterostomy procedure. MicroRNA-222 (miRNA) has been linked to the activation of stellate cells and the progression of liver fibrosis.

Methods: In this study, the miR-222 expression profile in BA and infants with anicteric choledochal cyst (CC) was determined. The functional effect of miR-222 inhibition on the growth of the human hepatic stellate cell line LX-2 was also evaluated. The downstream signaling pathways and target of miR-222 were determined by coupling gene expression profiling and pathway analysis and by in silico prediction, respectively. In addition, we demonstrated miR-222 overexpression in patients with BA compared with choledochal cyst controls.

Results: Inhibition of miR-222 in the LX-2 cell line significantly decreased cell proliferation. We also identified protein phosphatase 2A subunit B as a target of miR-222. The downstream signaling pathway, Akt, was also influenced by miR-222. A consistent reduction of Akt phosphorylation and Ki67 in the LX-2 line was shown following miR-222 suppression.

Conclusions: Our results show that miR-222 overexpression is common in BA and contributes to LX-2 cell proliferation by targeting protein phosphatase 2A subunit B and Akt signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biliary Atresia / metabolism
  • Biliary Atresia / pathology
  • Biliary Atresia / physiopathology*
  • Biliary Atresia / surgery
  • Cell Line
  • Cell Proliferation
  • Disease Progression
  • Female
  • Hepatic Stellate Cells / cytology
  • Hepatic Stellate Cells / metabolism
  • Hepatic Stellate Cells / pathology
  • Humans
  • Infant
  • Liver / metabolism*
  • Liver / pathology
  • Liver Cirrhosis / etiology*
  • Liver Cirrhosis / physiopathology
  • Male
  • MicroRNAs / metabolism*
  • Models, Biological*
  • Portoenterostomy, Hepatic
  • Prospective Studies
  • Protein Phosphatase 2 / antagonists & inhibitors*
  • Protein Phosphatase 2 / genetics
  • Protein Phosphatase 2 / metabolism
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • Signal Transduction
  • Up-Regulation*


  • MIRN222 microRNA, human
  • MicroRNAs
  • PPP2R2A protein, human
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt
  • Protein Phosphatase 2