Role of miR-148a in hepatitis B associated hepatocellular carcinoma

PLoS One. 2012;7(4):e35331. doi: 10.1371/journal.pone.0035331. Epub 2012 Apr 9.


Hepatitis B virus encoded X antigen (HBx) is a trans-regulatory protein that alters the activity of selected transcription factors and cytoplasmic signal transduction pathways. HBx transcriptionally up-regulates the expression of a unique gene, URG11, which in turn transcriptionally up-regulates β-catenin, thereby contributing importantly to hepatocarcinogenesis. HBx and URG11 also alter the expression of multiple microRNAs, and by miRNA array analysis, both were shown to promote the expression of miR-148a. Elevated miR-148a was also seen in HBx positive liver samples from infected patients. To study the function of miR-148a, anti-148a was introduced into HepG2 and Hep3B cells stably expressing HBx or stably over-expressing URG11. Anti-miR-148a suppressed cell proliferation, cell cycle progression, cell migration, anchorage independent growth in soft agar and subcutaneous tumor formation in SCID mice. Introduction of anti-miR-148a increased PTEN protein and mRNA expression, suggesting that PTEN was targeted by miR-148a. Anti-miR-148a failed to suppress PTEN expression when co-transfected with reporter gene mutants in the 3'UTR of PTEN mRNA. Introduction of anti-miR-148a also resulted in depressed Akt signaling by HBx and URG11, resulting in decreased expression of β-catenin. Thus, miR-148a may play a central role in HBx/URG11 mediated HCC, and may be an early diagnostic marker and/or therapeutic target associated with this tumor type.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3' Untranslated Regions
  • Adult
  • Aged
  • Animals
  • Carcinoma, Hepatocellular / diagnosis*
  • Carcinoma, Hepatocellular / virology*
  • Cell Cycle
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Female
  • Hepatitis B / metabolism*
  • Humans
  • Liver Neoplasms / diagnosis*
  • Liver Neoplasms / virology*
  • Male
  • Mice
  • Mice, SCID
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / metabolism*
  • Middle Aged
  • PTEN Phosphohydrolase / biosynthesis
  • Proto-Oncogene Proteins c-akt / metabolism
  • Trans-Activators / analysis
  • Trans-Activators / biosynthesis
  • Viral Regulatory and Accessory Proteins
  • beta Catenin / biosynthesis


  • 3' Untranslated Regions
  • CTNNB1 protein, human
  • MIRN148 microRNA, human
  • MicroRNAs
  • Trans-Activators
  • VWCE protein, human
  • Viral Regulatory and Accessory Proteins
  • beta Catenin
  • hepatitis B virus X protein
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human

Associated data

  • GEO/GSE33854