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

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.

• Authors: Jin-lan Huang, Ting-yu Ren, Shun-wang Cao, Shi-hao Zheng, Xiu-mei Hu, Yan-wei Hu, Li Lin, Jing Chen, Lei Zheng, Qian Wang
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 32 Pg. 33791-804 (Oct 20 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26393879 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Aged
• Animals
• Apoptosis
• Carcinoma, Hepatocellular (genetics, 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, 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