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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.

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Nucleolar assembly begins at the early G1 phase of the cell cycle and is a hub of ribosomal DNA transcription and rRNA biosynthesis. The newlyformed rRNAs together with ribosomal proteins (RPs) constitute the building block of the ribosomal machinery. Although RPs play a major role in protein biosynthesis, their own regulation and expression is rather poorly understood. In the present study, we investigated the regulation of RP genes RPS27a, RPS24, RPS6, RPL9 and RPL4 in synchronized mammalian cell culture. Quantitative RT-PCR analysis indicated their expression during the mid to late G1 phase, whereas the rRNA genes were expressed during the early G1 phase of the cell cycle. The promoter reporter analysis of the RPS27a gene revealed that it could be synergistically stimulated by the transcription factors specificity protein 1 (Sp1) and cAMP response element-binding protein (CREB). However, E2F transcription factor 1 (E2F1) appeared to negatively regulate gene expression. Chromatin immunoprecipitation studies confirmed the promoter occupancy of Sp1, CREB and E2F1. Although Sp1 and CREB binding enhanced the promoter occupancy of histone acetyltransferases PCAF, p300 and CREB binding protein, E2F1 facilitated the recruitment of histone deacetylases. Both acetylation (histone H4 pan-acetyl, histone H3 acetyl Lys 14) and methylation (histone H3 trimethyl Lys 9) marks were observed in the RPS27a promoter region, suggesting their important regulatory role in gene expression. Because the promoter regions of most RP genes are well conserved, we propose that their orchestrated regulation and synthesis during the cell cycle facilitates ribosome biogenesis.

a b s t r a c tThe nucleolus is a stress sensor associated with cell cycle progression and a viral target. However, the role of the nucleolus during hepatitis B virus infection has not been studied. Here we show that under nucleolar stress, the HBx oncoprotein down-regulates p53 and p21 waf1 levels by disrupting the interaction between ribosomal protein L11 and MDM2. Further, HBx inhibited Act D-mediated down-regulation of proliferat ive factors such as c-Myc and cyclin E and revived RNA pol I-dependent transcription under these conditions. Importantly, HBx also countered the action of anticancer drug Paclitaxel suggesti ng its possible role in drug resistance. Thus, HBx not only can facilitate cell proliferation under stress conditions but can confer resistance against anticancer drugs. Structured summary of protein interactions:RPL11 physically interacts with HBx and MDM2 by anti bait coimmunoprecipitation (View interaction) MDM2 physically inter acts with HBx by anti bait coimmunoprecipitation (View interaction) p53 physically interacts with HBx by anti bait coimmunoprecip itation (View interaction)