HBx-related long non-coding RNA DBH-AS1 promotes cell proliferation and survival by activating MAPK signaling in hepatocellular carcinoma

Oncotarget. 2015 Oct 20;6(32):33791-804. doi: 10.18632/oncotarget.5667.

Abstract

Accumulating evidence supports an important role for the hepatitis B virus x protein (HBx) in the pathogenesis of hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC), but the underlying mechanisms are not entirely clear. Here, we identified a novel long noncoding RNA (lncRNA) DBH-AS1 involved in the HBx-mediated hepatocarcinogenesis. The levels of DBH-AS1 were positively correlated with hepatitis B surface antigen (HBsAg) and tumor size in HCC tissues. Functionally, transgenic expression of DBH-AS1 significantly enhanced cell proliferation and tumorigenesis, whereas short hairpin RNA knockdown of DBH-AS1 caused an inhibition of cell proliferation. Mechanistically, overexpression of DBH-AS1 induced cell cycle progression by accelerating G1/S and G2/M transition concomitantly with upregulation of CDK6, CCND1, CCNE1 and downregulation of p16, p21 and p27. We also found that enhanced DBH-AS1 expression inhibited serum starvation-induced apoptosis of HCC cells. In contrast, suppressed DBH-AS1 expression had opposite effects. Furthermore, DBH-AS1 was shown to activate MAPK pathway. We also provide evidence that DBH-AS1 could be significantly induced by HBx protein and markedly down-regulated by p53. Thus, we concluded that DBH-AS1 can be induced by HBx and inactivated by p53, and consequently promote cell proliferation and cell survival through activation of MAPK signaling in HCC. Our study suggests that DBH-AS1 acts as an oncogene for HCC.

Keywords: DBH-AS1; HBx; HCC; lncRNA; proliferation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Apoptosis
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism*
  • Cell Cycle
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Cell Transformation, Neoplastic / genetics
  • Down-Regulation
  • Female
  • Gene Expression Regulation, Neoplastic
  • Hep G2 Cells
  • Hepatitis B Surface Antigens / metabolism*
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • MAP Kinase Signaling System*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Middle Aged
  • RNA Interference
  • RNA, Long Noncoding / genetics*
  • Signal Transduction
  • Trans-Activators / genetics*
  • Tumor Suppressor Protein p53 / metabolism
  • Viral Regulatory and Accessory Proteins

Substances

  • Hepatitis B Surface Antigens
  • RNA, Long Noncoding
  • TP53 protein, human
  • Trans-Activators
  • Tumor Suppressor Protein p53
  • Viral Regulatory and Accessory Proteins
  • hepatitis B virus X protein
  • long non-coding RNA DBH-AS1, human