title: Can tobacco use promote HCV-induced miR-122 hijacking and hepatocarcinogenesis?
abstract: Chronic hepatitis C virus (HCV) infection is a well-recognized risk factor for hepatocellular carcinoma (HCC). As a co-risk factor, the role of tobacco use in HCV-driven carcinogenesis and relevant underlying mechanisms remain largely unclear. The latest discoveries about HCV replication have shown that HCV RNA hijacks cellular miRNA-122 by forming an Ago2-HCV-miR-122 complex that stabilizes the HCV genome and enhances HCV replication. Our previous work has demonstrated that aqueous tobacco smoke extract (TSE) is a potent activator of HIV replication via TSE-mediated viral protection from oxidative stress and activation of a set of genes that can promote viral replication. Since HCV is, like HIV, an enveloped virus that should be equally susceptible to lipid peroxidation, and since one of the TSE-upregulated genes, the DDX3 helicase, is known to facilitate HCV replication, we hypothesize that (1) tobacco use can similarly enhance HCV viability and replication, and promote HCC progression by up-regulation of DDX3, and (2) by competing for binding with miR-122 as a competing endogenous RNA (ceRNA), HCV replication can liberate miR-122's direct target, oncogenic gene cyclin G1 (CCNG1); furthermore, simultaneous tobacco use can synergistically enhance this competing effect via HCV upregulation. Our hypotheses may lay a foundation for better understanding of carcinogenesis in HCV-driven HCC and the potential role of tobacco as a cofactor. Disrupting the HCV ceRNA effect may provide a new strategy for designing anti HCV/HCC drugs.
authors.affiliation: College of Life Sciences, Shaanxi Normal University, 199 South Chang'an Road, Xi'an 710062, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhao
authors.forename: Farong
authors.initials: F
authors.lastname: Li
authors.forename: Ethan Will
authors.initials: EW
authors.lastname: Taylor
mesh_terms: D060565:Argonaute Proteins; D006528:Carcinoma, Hepatocellular / Q000209:etiology*; D056766:Cyclin G1 / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism*; D019698:Hepatitis C, Chronic / Q000150:complications*; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology*; D035683:MicroRNAs / Q000378:metabolism*; D008954:Models, Biological; D014029:Tobacco Use Disorder / Q000150:complications*; D014779:Virus Replication / Q000502:physiology
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; C534702:CCNG1 protein, human; D056766:Cyclin G1; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; C119332:DDX3X protein, human; D053487:DEAD-box RNA Helicases