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Hypoxia-inducible factor 1 (HIF-1) emerges as a crucial player in tumor progression. However, its role in hepatocellular carcinoma (HCC), especially its relation with global DNA methylation patterns in HCC under hypoxic tumor microenvironment is not completely understood. Methionine adenosyltransferase 2A (MAT2A) maintains the homeostasis of S-adenosylmethionine (SAM), a critical marker of genomic methylation status. In this study, we investigated the link between HIF-1a and MAT2A as a mechanism responsible for the change in genomic DNA methylation patterns in liver cancer under hypoxia conditions. Our results showed that hypoxia induces genomic DNA demethylation in CpG islands by reducing the steady-state SAM level both in vitro and in vivo. In addition, HIF-1a and MAT2A expression is correlated with tumor size and TNM stage of liver cancer tissues. We further showed that hypoxia-induced MAT2A expression is HIF-1a dependent and requires the recruitment of p300 and HDAC1. We also identified an authentic consensus HIF1a binding site in MAT2A promoter by site-directed mutagenesis, electrophoretic mobility shift assay, and chromatin immunoprecipitation assay. Taken together, we show for the first time that hypoxia induces genomic DNA demethylation through the activation of HIF-1a and transcriptional upregulation of MAT2A in hepatoma cells. These findings provide new insights into our understanding of the molecular link between genomic DNA methylation and tumor hypoxia in HCC. Mol Cancer Ther; 10(6); 1113-23. Ó2011 AACR.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. Recent studies have demonstrated that long non-coding RNAs (lncRNAs) are key in carcinogenesis. The aim of the present study was to investigate the role of lncRNA GAS5 in HCC tissues and to define the role of growth arrest-specific 5 (GAS5) in the regulation of hepatoma cell proliferation, invasion and apoptosis. Quantitative polymerase chain reaction and in situ hybridization were performed to investigate the expression of GAS5 in tumor tissues and corresponding adjacent tissues from 50 patients with HCC. Low expression of GAS5 was significantly correlated with differentiation (P<0.010) and portal vein tumor thrombosis (P=0.001). Multivariate analysis indicated that GAS5 expression was an independent predictor for overall survival (P=0.017). Further experiments demonstrated that overexpression of GAS5 significantly suppressed the proliferation and invasion of hepatoma cells in vitro. Overexpression of GAS5 significantly promoted the apoptosis of hepatoma cells. In addition, it was demonstrated that GAS5 negatively regulates vimentin expression in vitro and in vivo. Notably, vimentin knockdown promoted GAS5-pcDNA3.1-inhibition of hepatoma cell proliferation. In conclusion, the present study suggests an important role of GAS5 in the molecular etiology of HCC and suggests the potential application of GAS5 in HCC therapy.

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We conclude that HIF-2alpha/EPAS1 expression may play an important role in tumor progression and prognosis of HCC. Assessment of HIF-2alpha/EPAS1 expression in HCC may be used as a diagnostic tool and possibly a target in the treatment of HCC.

BackgroundIn spite of progress in diagnostics and treatment of Hepatocellular Carcinoma (HCC), its prognosis remains poor, and improved treatment strategies for HCC require detailed understanding of the underlying mechanism. In this investigation we studied the role of Up-frameshift 1 (UPF1) in the tumorigenesis of HCC.MethodsWe determined the expression level of UPF1 in HCC tissues with quantitative real-time PCR and western blotting and then studied its clinical significance. Sodium bisulfite sequencing was used to investigate the regulation of UPF1. We explored the biological significance of UPF1 with gain-and-loss-of-function analyses both in vitro and in vivo. The relationship between UPF1 and SMAD7 was also investigated by western blotting and immunofluorescence.ResultsA great downregulation of UPF1 due to promoter hypermethylation was observed in tumor tissues compared to their adjacent normal tissues. Meanwhile, patients with low UPF1 expression have significantly poorer prognosis than those with high expression. Functionally, UPF1 regulated HCC tumorigenesis both in vitro and in vivo. Moreover, the decreased UPF1 level in HCC reduces NMD efficiency and leads to up-regulation of Smad7, then affects the TGF-β pathway.ConclusionOur findings revealed that UPF1 is a potential tumor suppressive gene and may be a potential therapeutic target for HCC.

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Background. The association between human endogenous retroviruses-K (HERV-K) (HML-2) and human disease, including a variety of cancers, has been indicated. However, the function of HERV-K (HML-2) in the progression of hepatocellular carcinoma (HCC) still remains largely unclear. Methods. We detected the expression of HERV-K (HML-2) in 84 HCC tissues and adjacent nontumor tissues by quantitative real-time PCR (qRT-PCR) and analyzed its correlation with the clinical parameters. Result. The HEVR-K level was significantly increased in HCC compared with adjacent normal tissues (P < 0.01) which was proved to be significantly associated with cirrhosis (P < 0.05), tumor differentiation (P < 0.05), and TNM stage (P < 0.05). Moreover, the high expression of HERV-K (HML-2) had a poorer overall survival than patients with lower expression by a Kaplan-Meier survival analysis (P < 0.01). The multivariate Cox regression analysis indicated that the level of HERV-K (HML-2) was an independent prognostic factor for the overall survival rate of HCC patients. Receiver operating characteristic (ROC) curves demonstrated the diagnostic accuracy of HERV-K (HML-2) expression in HCC (AUC = 0.729, 74.7% sensitivity, and 67.8% specificity). Conclusions. Our results suggested that upregulation of HERV-K (HML-2) in HCC patients was significantly related to cancer progression and poor outcome, indicating that HERV-K (HML-2) might be a novel candidate prognostic biomarker for HCC.