Hepatotropic viruses such as hepatitis B virus (HBV) and hepatitis C virus (HCV) are the major etiological agents associated with development of hepatocellular carcinoma (HCC). Progression of HCC is a multistep process that requires sequential or parallel deregulation of oncogenic and tumor suppressive pathways leading to chromosomal instability and neoplastic phenotype. In the recent years, microRNAs (miRNAs) have carved their own niche alongside oncogenes and tumor suppressors, owing to their innate ability to receive and relay multiple signals. Not surprisingly, miRNAs are fast emerging as central player in myriads of malignancies including HCC. miRNAs are reported to participate in initiation and progression of HCC, and have also been clinically correlated with risk assessment, disease grade, aggressiveness, and prognosis. Despite extensive data available on the role of miRNAs in HCC, there is a pressing need to integrate and evaluate these datasets to find its correlation, if any, with causal agents in order to devise novel interventional modalities. Through this review, we attempt to bridge the gap by consolidating the current knowledge and concepts in the field of HCC-related miRNAs with special emphasis on HBV and HCV. Further, we assess the potential of common as well as unique signatures that may be useful in developing novel biomarkers and therapeutics.
Background: CDC6 is a replication licensing factor, which is tightly regulated to prevent reinitiation of replication. Results: Hepatitis B virus HBx protein up-regulates CDC6 both transcriptionally as well as post-transcriptionally and promotes its recruitment to -globin origin of replication. Conclusion: Accumulation of CDC6 protein under HBx microenvironment facilitates origin licensing. Significance: Deregulation of replication factors could be a mechanism associated with viral oncogenesis.
Highlightsd The CIA-targeting complex interacts with, but is not a substrate of, FBXL5d The CTBD domain of FBXL5 is critical for interaction with the CIA-targeting complex d The CIA-targeting complex stimulates FBXL5-mediated polyubiquitination of IRPs d O 2 levels regulate the FBXL5-CIA-targeting complex interaction
Sirtuin-7 (SIRT7) deacetylase exhibits a high selectivity for acetylated H3K18 and has been implicated in the maintenance of malignant phenotype. However, it remains unclear if SIRT7 and H3K18ac play a role in the tumorigenic program driven by oncogenic viruses. We show that ectopically expressed HBx oncoprotein of hepatitis B virus promoted intracellular stability of SIRT7 by salvaging it from ubiquitin-mediated proteasomal degradation. HBx-dependent accumulation of SIRT7 favored H3K18 deacetylation and down-regulated the small ribosomal protein gene, RPS7, involved in cell death and DNA damage response. HBx facilitated the recruitment of SIRT7 to RPS7 promoter thus impeding H3K18ac occupancy and hindering RPS7 transcription. The antagonistic relationship between SIRT7 and RPS7 was also observed in the HBx transgenic mice, where elevated levels of SIRT7 protein were coincident with low levels of H3K18ac and RPS7. Strikingly, inhibition of cellular deubiquitinase activity restored RPS7 gene transcription. Further, depletion of endogenous SIRT7 led to decreased cell viability and transformation. The biological relevance of RPS7 suppression by HBx-SIRT7 axis was evident from ectopic expression of RPS7 which attenuated clonogenicity of cells. Thus, our findings suggest that SIRT7 is a critical regulator of HBx-driven oncogenic program, through its antagonistic impact on growth restrictive ribosomal protein RPS7.
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