miRNA-548p suppresses hepatitis B virus X protein associated hepatocellular carcinoma by downregulating oncoprotein hepatitis B x-interacting protein

Aim miR‐548p is a recently identified and poorly characterized miRNA. However, its role of miR‐548p in tumorigenesis and progression remains poorly understood. Here, we aimed to investigate the biofunction of miR‐548p in hepatocellular carcinogenesis. Methods The expression levels of miR‐548p were detected by quantitative reverse transcription polymerase chain reaction (qRT–PCR). The role of miR‐548p in hepatocellular carcinoma (HCC) was determined by colony formation, flow cytometry assay and nude mice xenograft experiments. miR‐548p target genes were analyzed by miRNA target predication programs and verified by qRT–PCR, western blotting assay and dual‐luciferase reporter assay. Results miR‐548p is repressed by hepatitis B virus X protein (HBx) in HCC tumor tissues and hepatoma cells, and inhibited cell growth by inhibiting cell proliferation and promoting cell apoptosis. miR‐548p directly downregulated the expression of hepatitis B x‐interacting protein (HBXIP) by binding to the 3′‐untranslated region of HBXIP mRNA. Further study showed that hepatocyte nuclear factor‐4a (HNF4A) promoted the expression of miR‐548p and inhibited the transcription of HBXIP. HNF4A is a dominant transcriptional regulator of hepatocyte differentiation and hepatocellular carcinogenesis, and is shown to be repressed by HBx. Conclusion We proposed the model for HBx/HNF4A/miR‐548p/HBXIP pathway that controls hepatoma cell growth and tumorigenesis of HCC. miR‐548p was identified as a tumor‐suppressor in HBx‐associated hepatocellular carcinogenesis.