HBx elevates oncoprotein AEG-1 expression to promote cell migration by downregulating miR-375 and miR-136 in malignant hepatocytes

DNA Cell Biol. 2014 Oct;33(10):715-22. doi: 10.1089/dna.2014.2376. Epub 2014 Jul 22.

Abstract

The hepatitis B viral X protein (HBx) has been established to implicate in the development of HBV-related hepatocellular carcinoma (HCC) via multiple pathways. The oncoprotein astrocyte elevated gene-1 (AEG-1) is overexpressed in various tumors, including HCC, and plays critical roles in promoting cell migration and invasion. However, the mechanisms for AEG-1 upregulation in tumors are largely unknown. In this study, we found that HBx could elevate AEG-1 protein level without altering its mRNA level. When blocking AEG-1 expression with siRNA in HBx-transfected cells, the HBx-induced cell migration was significantly suppressed. Further study indicated that miR-375 and miR-136 that targeted AEG-1 were downregulated with HBx expression. Overexpressing miR-375 and miR-136 could effectively attenuate HBx-mediated AEG-1 elevation and cell migration. These results demonstrated that HBx enabled to increase oncoprotein AEG-1 expression to promote cell migration via downregulating miR-375 and miR-136. Our findings provide a novel insight into AEG-1 upregulation in HCC and shed new light on HBx promoting HCC progression. Meanwhile, our results also suggest that miR-375 and miR-136 may have the miRNA-based therapeutic potential in HBV-associated HCC.

Publication types

  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / virology*
  • Cell Adhesion Molecules / biosynthesis*
  • Cell Adhesion Molecules / genetics
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Down-Regulation
  • Hep G2 Cells
  • Hepatitis B virus / genetics
  • Hepatitis B, Chronic / complications
  • Hepatitis B, Chronic / pathology
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / pathology
  • Liver Neoplasms / virology*
  • Membrane Proteins
  • MicroRNAs / biosynthesis*
  • Neoplasm Invasiveness
  • RNA Interference
  • RNA, Messenger / biosynthesis
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • Trans-Activators / biosynthesis
  • Trans-Activators / metabolism*
  • Transcription, Genetic
  • Up-Regulation
  • Viral Regulatory and Accessory Proteins

Substances

  • Cell Adhesion Molecules
  • MIRN136 microRNA, human
  • MIRN375 microRNA, human
  • MTDH protein, human
  • Membrane Proteins
  • MicroRNAs
  • RNA, Messenger
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • Trans-Activators
  • Viral Regulatory and Accessory Proteins
  • hepatitis B virus X protein