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

// Jin-lan Huang 1,* , Ting-yu Ren 1,* , Shun-wang Cao 1 , Shi-hao Zheng 2 , Xiu-mei Hu 1 , Yan-wei Hu 1 , Li Lin 1 , Jing Chen 1 , Lei Zheng 1 and Qian Wang 1 1 Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China 2 Department of Neurosurgery, Fujian Provincial Hospital, Fuzhou, Fujian, China * These authors have contributed equally to this work Correspondence to: Qian Wang, email: // Lei Zheng, email: // Keywords : lncRNA, DBH-AS1, HCC, proliferation, HBx Received : March 04, 2015 Accepted : August 23, 2015 Published : September 15, 2015 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.