Role of miR-148a in Hepatitis B Associated Hepatocellular Carcinoma
Open Access
- 9 April 2012
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 7 (4), e35331
- https://doi.org/10.1371/journal.pone.0035331
Abstract
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.Keywords
This publication has 64 references indexed in Scilit:
- TGF-β activates Akt kinase through a microRNA-dependent amplifying circuit targeting PTENNature Cell Biology, 2009
- Regulation of Mammary Stem/Progenitor Cells by PTEN/Akt/β-Catenin SignalingPLoS Biology, 2009
- Putative roles of hepatitis B x antigen in the pathogenesis of chronic liver diseaseCancer Letters, 2009
- PTEN and the PI3-Kinase Pathway in CancerAnnual Review Of Pathology-Mechanisms Of Disease, 2009
- A microRNA DNA methylation signature for human cancer metastasisProceedings of the National Academy of Sciences, 2008
- miR-148 targets human DNMT3b protein coding regionRNA, 2008
- MicroRNA-21 Regulates Expression of the PTEN Tumor Suppressor Gene in Human Hepatocellular CancerGastroenterology, 2007
- Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesisNature Reviews Cancer, 2006
- MicroRNA expression profiles classify human cancersNature, 2005
- A microRNA polycistron as a potential human oncogeneNature, 2005