The involvement of the hepatitis B virus X (HBx) protein in epigenetic modifications during hepatocarcinogenesis has been previously characterized. Long noncoding RNAs (lncRNAs), a kind of epigenetic regulator molecules, have also been shown to play crucial roles in HBx-related hepatocellular carcinoma (HCC). In this study, we analyzed the key transcription factors of aberrantly expressed lncRNAs in the livers of HBx transgenic mice by bioinformatics prediction, and found that ecotropic viral integration site 1 (Evi1) was a potential main transcription regulator. Further investigation showed that EVI1 was positively correlated to HBx expression and was frequently up-regulated in HBV-related HCC tissues. The forced expression of HBx in liver cell lines resulted in a significant increase of the expression of EVI1. Furthermore, suppression of EVI1 expression decreased the proliferation of HCC cells overexpressing HBx in vitro and in vivo.
Conclusion: Our findings suggest that EVI1 is frequently up-regulated and regulates a cluster of lncRNAs in HBV-related hepatocellular carcinoma (HCC). These findings highlight a novel mechanism for HBx-induced hepatocarcinogenesis through transcription factor EVI1 and its target lncRNAs, and provide a potential new approach to predict the functions of lncRNAs.
Keywords: ecotropic viral integration site 1; hepatitis B virus X protein; hepatocellular carcinoma; long non-coding RNA; transcription factor.