title: Role of miR-148a in hepatitis B associated hepatocellular carcinoma.
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.
authors.affiliation: Department of Biology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Ke
authors.initials: K
authors.lastname: Yuan
authors.forename: Zhaorui
authors.initials: Z
authors.lastname: Lian
authors.forename: Bill
authors.initials: B
authors.lastname: Sun
authors.forename: Marcia M
authors.initials: MM
authors.lastname: Clayton
authors.forename: Irene O L
authors.initials: IO
authors.lastname: Ng
authors.forename: Mark A
authors.initials: MA
authors.lastname: Feitelson
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D000368:Aged; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis* / Q000821:virology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D006509:Hepatitis B / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000175:diagnosis* / Q000821:virology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015534:Trans-Activators / Q000032:analysis / Q000096:biosynthesis; D054334:Viral Regulatory and Accessory Proteins; D051176:beta Catenin / Q000096:biosynthesis
chemical_list: D020413:3' Untranslated Regions; C495270:CTNNB1 protein, human; C550570:MIRN148 microRNA, human; D035683:MicroRNAs; D015534:Trans-Activators; C547681:VWCE protein, human; D054334:Viral Regulatory and Accessory Proteins; D051176:beta Catenin; C057628:hepatitis B virus X protein; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human