RESUMO
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-ß-induced factor homeobox 2 (TGIF2), a transcription factor repressing transforming growth factor-ß (TGFß) 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.
RESUMO
microRNAs (miRNAs) are short, non-coding RNAs with post-transcriptional regulatory functions that participate in diverse biological pathways. miR-122, a liver-specific miRNA, has been found to be down-regulated in hepatocellular carcinoma (HCC) and HCC-derived cell lines. In this study, miR-122 was down-regulated in the hepatitis B virus (HBV)-related HCC cell line HepG2.2.15 compared to HepG2. NDRG3, a member of the N-myc downstream-regulated gene (NDRG) family, was up-regulated in HepG2.2.15 and was identified as a target gene of miR-122. An inverse correlation between the expression of miR-122 and the NDRG3 protein was noted in HBV-related HCC specimens. The transfection of the miR-122 expression vector into the HepG2.2.15 cell line repressed the transcription and expression of NDRG3, which subsequently reversed the malignant phenotype of the cells. The replication of HBV, expression of viral antigens and proliferation of cells were significantly inhibited by restoration of miR-122. The data demonstrate that miR-122 plays an important role in HBV-related hepatocarcinogenesis by targeting NDRG3. Thus, miR-122 and NDRG3 represent key diagnostic markers and potential therapeutic targets for HBV-related HCC.
Assuntos
Carcinoma Hepatocelular/virologia , Vírus da Hepatite B/fisiologia , Neoplasias Hepáticas/virologia , MicroRNAs/genética , Proteínas do Tecido Nervoso/genética , Animais , Sequência de Bases , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Processos de Crescimento Celular/genética , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , MicroRNAs/biossíntese , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/biossíntese , Transfecção , Replicação Viral/genéticaRESUMO
Recent studies have revealed that microRNA-29c (miR-29c) is involved in a variety of biological processes including carcinogenesis. Here, we report that miR-29c was significantly downregulated in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) cell lines as well as in clinical tissues compared with their corresponding controls. Tumor necrosis factor alpha-induced protein 3 (TNFAIP3), a key regulator in inflammation and immunity, was found to be inversely correlated with miR-29c levels and was identified as a target of miR-29c. Overexpression of miR-29c in HepG2.2.15 cells effectively suppressed TNFAIP3 expression and HBV DNA replication as well as inhibited cell proliferation and induced apoptosis. We conclude that miR-29c may play an important role as a tumor suppressive microRNA in the development and progression of HBV-related HCC by targeting TNFAIP3. Thus miR-29c and TNFAIP3 represent key diagnostic markers and potential therapeutic targets for the prevention and treatment of HBV infection.
