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Hepatocytes are the target host cells during hepatitis B virus (HBV) infection. Recent studies indicate that the innate immune response of hepatocytes plays an important role in inhibiting HBV replication. TIR-domain-containing adaptor inducing interferon-beta (TRIF) is a key component in innate immune signaling pathways. In this study, we found that the TRIF protein was downregulated in human hepatoma cell lines and liver tissue samples harboring HBV. Hepatitis B virus X protein (HBX) reduced TRIF protein expression in a dose-dependent manner via the proteasomal pathway. HBX appeared to not directly interact with TRIF as these proteins failed to co-immunoprecipitate when overexpressed in hepatoma cells. TRIF upregulation in hepatoma cell lines dramatically inhibited HBV transcription and expression of its viral proteins. Cellular apoptosis induced by TRIF was also confirmed in hepatoma cell lines. Taken together, these findings reveal a new mechanism for HBV evasion of the cellular innate immunity by HBX-mediated degradation of TRIF protein in hepatocytes. [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 tumor suppressor p53 modulates transcription of a number of target genes involved in cell cycle arrest, apoptosis, DNA repair, and other important cellular responses. Mitofusin-2 (Mfn2) is a novel suppressor of cell proliferation that may also exert apoptotic effects via the mitochondrial apoptotic pathway. Through bioinformatics analysis, we identified a p53 binding site in the Mfn2 promoter. Consistent with this, we showed that the p53 protein binds the Mfn2 promoter directly both in vitro and in vivo. Additionally, we found that Mfn2 mRNA and protein levels are up-regulated in a p53-dependent manner. Furthermore, luciferase assays revealed that the activity of the wild-type Mfn2 promoter, but not a mutated version of the promoter, was up-regulated by p53. These results indicate that Mfn2 is a novel p53-inducible target gene, which provides insight into the regulation of Mfn2 and its associated activities in the inhibition of cell proliferation, promotion of apoptosis, and modulation of tumor suppression. [ABSTRACT FROM AUTHOR]