RESUMO
Hepatocellular carcinoma (HCC) is one of the world's leading fatal malignancies. Chronic infection with the hepatitis B virus (HBV) has been implicated with the development of HCC. For the past three decades, intensive research has focused on the role of HBV in hepatocarcinogenesis. Various HBV-associated models have emerged, but increasing evidence points to two major HBV-specific mechanisms that contribute to the development of HCC. The first is the integration of the viral genome into the host chromosome causing cis-effects, resulting in loss of tumor suppressor gene functions, and/or activation of tumor-promoting genes. The second mechanism involves the expression of trans-activating factors derived from the HBV genome, which have the potential to influence intracellular signal transduction pathways and alter host gene expression. A major player involved in this form of viral transactivation is the X protein (HBx). The HBx protein was found to display pleiotropic functions and has been implicated in the malignant transformation of chronically-infected liver cells. By disrupting cellular gene expression, viral products such as HBx may modulate cellular growth, repair and death, consequently resulting in the transformation of hepatocytes to an oncogenic state.
Assuntos
Carcinoma Hepatocelular/virologia , Hepacivirus/patogenicidade , Hepatite C Crônica/virologia , Neoplasias Hepáticas/virologia , Carcinoma Hepatocelular/genética , Transformação Celular Viral , Hepacivirus/genética , Humanos , Neoplasias Hepáticas/genética , Vírus Oncogênicos/patogenicidadeRESUMO
Like other cancers, aberrant gene regulation features significantly in hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) were recently found to regulate gene expression at the post-transcriptional/translational levels. The expression profiles of 157 miRNAs were examined in 19 HCC patients, and 19 up-regulated and 3 down-regulated miRNAs were found to be associated with HCC. Putative gene targets of these 22 miRNAs were predicted in silico and were significantly enriched in 34 biological pathways, most of which are frequently dysregulated during carcinogenesis. Further characterization of microRNA-224 (miR-224), the most significantly up-regulated miRNA in HCC patients, revealed that miR-224 increases apoptotic cell death as well as proliferation and targets apoptosis inhibitor-5 (API-5) to inhibit API-5 transcript expression. Significantly, miR-224 expression was found to be inversely correlated with API-5 expression in HCC patients (p < 0.05). Hence, our findings define a true in vivo target of miR-224 and reaffirm the important role of miRNAs in the dysregulation of cellular processes that may ultimately lead to tumorigenesis.
Assuntos
Proteínas Reguladoras de Apoptose/genética , Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica/genética , MicroRNAs/genética , Proteínas Nucleares/genética , Regulação para Cima/genética , Apoptose , Sequência de Bases , Carcinoma Hepatocelular/patologia , Transformação Celular Neoplásica/genética , Perfilação da Expressão Gênica , Humanos , Dados de Sequência Molecular , Especificidade por Substrato , Transcrição Gênica/genética , Células Tumorais CultivadasRESUMO
Various reports have implicated the virally encoded HBx protein as a cofactor in hepatocarcinogenesis. However, direct evidence of the role of HBx as a promoter of oncogenesis in response to an initiating factor such as DNA damage remains inadequate. Here, we report the effects of HBx in HepG2 cells exposed to UV light-induced DNA damage. HBx expression was found not to affect the morphology, viability, and cell cycle/apoptotic profiles or DNA repair machinery of untreated cells. Nonetheless, upon UV treatment, HBx protein levels increased concomitantly with p53 levels. Both HBx and p53 proteins were found to interact and colocalize primarily in the nucleus. The binding of HBx to p53 modulated (but did not inhibit) the transcriptional activation function of p53. Notably, HBx-expressing cells exhibited increased sensitivity to UV damage, resulting in greater G2/M arrest and apoptosis of these cells. Additionally, these cells displayed a reduced DNA repair capacity in response to UV damage. In conclusion, this work suggests that DNA damage may be an initiating factor in hepatocarcinogenesis and that HBx may act as the promoting factor by inhibiting DNA repair. In hepatitis B virus-infected hepatocytes, a chronic infection may present the opportunity for such a DNA-damaging event to occur, and accumulated errors caused by the inhibition of DNA repair by HBx may result in oncogenesis.