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As the sixth most prevalent cancer, hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Human replication protein A (RPA), a three-subunit protein, plays a central role in eukaryotic DNA replication, homologous recombination, and excision repair, including RPA1, RPA2 and RPA3. Recently, some studies focusing on the relation between RPA1 and carcinogenesis have demonstrated that RPA1 is a candidate oncogene and influences tumor biological behaviors in many cancers such as esophageal carcinoma, colon cancer, urothelial carcinomas, etc. However, the characteristic role of RPA1 in HCC and the detailed potential mechanism remain unknown. To identify the real effects of RPA1 on HCC and its potential pathway participating in the changes of liver cancer cells, we have conducted this study and demonstrated that RPA1 is up-regulated both in liver cancer cell lines and HCC tissues, which is associated with poorer prognosis, advanced TNM stage and larger tumor size. Stable knock-down of RPA1 by specific small hairpin RNA (shRNA) contributes to the impaired proliferate ability of SK-HEP-1 cells both in vitro and vivo. Consistently, upregulation of RPA1 in HuH-7 cells by specific adenovirus promotes tumor cells' proliferation. Furthermore, cyclin-dependent-kinase 4(CDK4)/Cyclin-D pathway is found to be well associated with RPA1 induced proliferation. In conclusion, RPA1 plays a pivotal role as a potential oncogene in HCC and promotes tumor proliferation via CDK4/Cyclin-D pathway. [ABSTRACT FROM AUTHOR]

Chronic infection with hepatitis B virus (HBV) plays an important role in the etiology of hepatocellular carcinoma (HCC). Signal transducer and activator of transcription 3 (STAT3) inactivation could inhibit the tumor growth of HCC. In this study, differential antiproliferative effect of STAT3 inhibition was observed with HBV-related HCC cells being more resistant than non-HBV-related HCC cells. Resistance of HBV-related HCC cells to STAT3 inhibition was positively correlated to the expression of HBV. Enhanced ERK activation after STAT3 blockade was detected in HBV-related HCC cells but not in non-HBV-related HCC cells. Combined ERK and STAT3 inhibition eliminates the discrepancy between the two types of HCC cells. Moderate reduced HBV expression was found after STAT3 inhibition. These findings disclose a discrepancy in cellular response to STAT3 inhibition between non-HBV-related and HBV-related HCC cells and underscore the complexity of antiproliferative effect of STAT3 inactivation in HBV-related HCC cells. [ABSTRACT FROM AUTHOR]

Abstract: The hepatitis B virus X (HBx) protein has many significant roles in hepatocellular carcinoma (HCC). Our previous research demonstrated that mitofusion-2 (Mfn2), a potential tumor suppressor gene in HCC, is a novel direct target of p53 that exerts apoptotic effects via the mitochondrial apoptotic pathway. However, the relationship between HBx and Mfn2 expression in the development of HCC is unknown. We found that HBx had little direct effect on the expression of Mfn2 or p53 in HCC cells not treated with doxorubicin. However, HBx inhibited the upregulation of Mfn2 in HBx-transfected HCC cells simultaneously treated with doxorubicin or cotransfected with p53 plasmid, as evidenced by Western Blot and real-time PCR. Through electrophoretic mobility shift analysis, we confirmed that HBx interfered with the binding event of the p53 protein and the p53 binding site-oligo of the Mfn2 promoter. Moreover, luciferase assays revealed that the activity of the Mfn2 promoter did not increase when transfected with HBx plasmid in doxorubicin-treated HepG2 cells. These results indicate that HBx impacts p53-mediated transcription of Mfn2, providing insight into the negative effect of HBx against p53-dependent chemotherapeutic agents, such as doxorubicin, used in the treatment of HCC. [Copyright &y& Elsevier]