Abstract
MicroRNAs (miRs) are short, non-coding RNAs with post-transcriptional regulatory functions. Previous studies have demonstrated that miR-34c is involved in diverse biological processes, including carcinogenesis. The aim of the present study was to investigate the role of miR-34c and its target genes in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Expression levels of miR-34c and its predicted target genes were measured. The target genes were validated by a luciferase assay. The effects of miR-34c restoration were evaluated by the detection of HBV antigens, cell proliferation and apoptosis in vitro, in addition to the tumor growth in vivo. The data demonstrated that miR-34c was downregulated in HBV-associated HCC clinical tissues and HCC cell lines compared with their corresponding controls. transforming growth factor-β-induced factor homeobox 2 (TGIF2), a transcription factor repressing transforming growth factor-β (TGFβ) signaling, was observed to be upregulated and was identified as a target gene of miR-34c. The restoration of miR-34c in HepG2.2.15 cells suppressed TGIF2 expression, HBV replication and viral antigen synthesis; inhibited cell proliferation; and induced apoptosis. miR-34c also inhibited tumor growth in a mouse model. The present study indicates that miR-34c may act as a tumor suppressor by targeting TGIF2 during HBV-associated hepatocellular carcinogenesis. miR-34c and TGIF2 may represent key regulatory factors, diagnostic markers and therapeutic targets for the prevention and treatment of HBV-associated HCC.
Highlights
Previous epidemiological studies have demonstrated that hepatitis B virus (HBV) infection is a key risk factor for hepatocellular carcinoma (HCC)
QPCR revealed that miR‐34c was downregulated in HBV‐related HCC tissues compared with adjacent non‐cancerous liver tissues (Fig. 1A)
Certain mammalian miRs have been identified that exhibit antiviral effects [9]. miR‐34c is involved in negative feedback control of the cell cycle, including cell cycle arrest, senescence and apoptosis
Summary
Previous epidemiological studies have demonstrated that hepatitis B virus (HBV) infection is a key risk factor for hepatocellular carcinoma (HCC). HBV is greatly detrimental to human health by inducing hepatitis, cirrhosis and HCC [1]. The currently available diagnostic methods, including B‐mode ultrasound and α‐fetal protein (AFP) detection, lack the ability to detect liver cancer at an early stage [2,3]. Therapy is currently only partially effective against HBV. Investigation into the pathogenesis of HBV‐related HCC is of great significance. Studies on microRNAs (miRs) may provide a valuable approach for devising novel strategies for the diagnosis, prevention and treatment of HCC
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