HCV-Derived Non-coding RNA Induces Proteins that Promote Transformation of Differentiated Hepatocytes Open Access
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Introduction: Hepatitis C virus (HCV) infection remains a major health concern worldwide due to the lack of preventative care and associated health risks, despite having therapeutic treatments. One of the most critical risks associated with HCV is the development of hepatocellular carcinoma (HCC), yet the mechanisms of HCV-mediated hepatocarcinogenesis remain unclear. Here, we determine if HCV1a associated non-coding RNA, vmr11 induces oncogenic phenotypes and protein expression deregulation in infected hepatocytes. We explore the inhibitory capabilities of anti-vmr11 and show viral RNA driving oncogenic properties and anti-vmr11 suppressing the effects.Methods: Differentiated hepatocytes were transfected with HCV1a (H77), vmr11-mimic, anti-vmr11, or a combination of viral RNA (H77 or vmr11-mimic) with anti-vmr11. Assays were performed to determine the effect of viral RNA and anti-vmr11 on cellular properties including cell proliferation, cell migration and invasion, and anchorage-independent growth. Changes in intracellular proteome affected by viral RNA were evaluated by quantitative comparative proteomics (SILAC).Results: Viral RNA induced changes in cellular properties, namely cell proliferation, migration and invasion, and colony formation capabilities which were inhibited by co-transfection of anti-vmr11. Proteomic quantitation revealed deregulation in proteins involved in numerous biochemical functions, including chromatin remodeling, RNA binding, protein transport, and lipid metabolism.Conclusions: Our results suggest HCV1a and vmr11-mimc induced cellular changes favorable to oncogenic transformation of differentiated human hepatocytes that can be inhibited by anti-vmr11. Furthermore, viral RNA promoted deregulation of known and novel proteins including those likely necessary for HCV replication. Of those proteins, our results indicate novel interactions with HCV1a. The results also suggest novel antisense oligonucleotide-based intervention of hepatocarcinogenesis.