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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.

SUBMITTER: Huang JL

PROVIDER: S-EPMC4741803 | biostudies-other | 2015 Oct

REPOSITORIES: biostudies-other

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

Huang Jin-lan JL Ren Ting-yu TY Cao Shun-wang SW Zheng Shi-hao SH Hu Xiu-mei XM Hu Yan-wei YW Lin Li L Chen Jing J Zheng Lei L Wang Qian Q

Oncotarget 20151001 32

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 express ...[more]

PMID: 26393879

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Project description:BackgroundLong non-coding RNAs (lncRNAs) are widely involved in human cancers' progression by regulating tumor cells' various malignant behaviors. MAPKAPK5-AS1 has been recognized as an oncogene in colorectal cancer. However, the biological role of MAPKAPK5-AS1 in hepatocellular carcinoma (HCC) has not been explored.MethodsQuantitative real-time PCR was performed to detect the level of MAPKAPK5-AS1 in HCC tissues and cell lines. The effects of MAPKAPK5-AS1 on tumor growth and metastasis were assessed via in vitro experiments, including MTT, colony formation, EdU, flow cytometry, transwell assays, and nude mice models. The western blotting analysis was carried out to determine epithelial-mesenchymal transition (EMT) markers and AKT signaling. The interaction between MAPKAPK5-AS1, miR-154-5p, and PLAGL2 were explored by luciferase reporter assay and RNA immunoprecipitation. The regulatory effect of HIF-1? on MAPKAPK5-AS1 was evaluated by chromatin immunoprecipitation.ResultsMAPKAPK5-AS1 expression was significantly elevated in HCC, and its overexpression associated with malignant clinical features and reduced survival. Functionally, MAPKAPK5-AS1 knockdown repressed the proliferation, mobility, and EMT of HCC cells and induced apoptosis. Ectopic expression of MAPKAPK5-AS1 contributed to HCC cell proliferation and invasion in vitro. Furthermore, MAPKAPK5-AS1 silencing suppressed, while MAPKAPK5-AS1 overexpression enhanced HCC growth and lung metastasis in vivo. Mechanistically, MAPKAPK5-AS1 upregulated PLAG1 like zinc finger 2 (PLAGL2) expression by acting as an endogenous competing RNA (ceRNA) to sponge miR-154-5p, thereby activating EGFR/AKT signaling. Importantly, rescue experiments demonstrated that the miR-154-5p/PLAGL2 axis mediated the function of MAPKAPK5-AS1 in HCC cells. Interestingly, we found that hypoxia-inducible factor 1? (HIF-1?), a transcript factor, could directly bind to the promoter to activate MAPKAPK5-AS1 transcription. MAPKAPK5-AS1 regulated HIF-1? expression through PLAGL2 to form a hypoxia-mediated MAPKAPK5-AS1/PLAGL2/HIF-1? signaling loop in HCC.ConclusionsOur results reveal a MAPKAPK5-AS1/PLAGL2/HIF-1? signaling loop in HCC progression and suggest that MAPKAPK5-AS1 could be a potential novel therapeutic target of HCC.

Project description:Recent evidence has proven that long noncoding RNAs (lncRNAs) play important roles in cancer biology, while few lncRNAs have been characterized in NSCLC. Here, we characterized a novel lncRNA, SBF2 antisense RNA 1 (SBF2-AS1), in non-small cell lung cancer (NSCLC).Quantitative real-time PCR was used to quantify SBF2-AS1 expression in NSCLC tissues and cell lines. The correlation of SBF2-AS1 expression with clinicopathologic features was analyzed in a cohort NSCLC patient. Loss of function and gain of function studies were performed to determine the effects of SBF2-AS1 on proliferation and metastasis of NSCLC cells. RNA immunoprecipitation and chromosome immunoprecipitation assay was performed to confirm the interaction between SBF2-AS1 with protein and chromosome.We confirmed that SBF2-AS1 was significantly upregulated in NSCLC compared with corresponding non-tumor tissues, and a high expression level of SBF2-AS1 was correlated with lymph node metastasis and advanced TNM stage. Using siRNAs specifically targeting SBF2-AS1 and plasmid vector, we successfully silenced and overexpressed SBF2-AS1 in NSCCLC cell lines and investigated its biological function both in vitro and in vivo. After the silencing of SBF2-AS1, the metastasis of NSCLC cells was significantly inhibited, the silencing of SBF2-AS1 decreased the proliferation of NSCLC cells, and the cell cycle was arrested at the G1 phase; while overexpression promoted proliferation ability. Xenograft tumor models revealed that the silencing of SBF2-AS1 inhibited tumor growth in vivo. We speculated that SBF2-AS1 might negatively regulate P21. RNA immunoprecipitation discovered that SBF2-AS2 could bind with a core component of polycomb repressive complex2, SUZ12. Additionally chromatin immunoprecipitation assay demonstrated that, after silencing SBF2-AS1, the enrichment of SUZ12 and trimethylation of histone 3 lysine 27 decreased at the promoter region of P21.We demonstrated that SBF2-AS1 is upregulated in NSCLC and promotes proliferation of NSCLC tumor cells. SBF2-AS1 may serve as a novel biomarker and potential therapeutic target for NSCLC patients.

Dataset Information

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

Publications

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

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