HCV Proteins Modulate the Host Cell miRNA Expression Contributing to Hepatitis C Pathogenesis and Hepatocellular Carcinoma Development

Abstract

Hepatitis C virus (HCV) genome encodes for one long polyprotein that is processed by cellular and viral proteases to generate 10 polypeptides. The viral structural proteins include the core protein, and the envelope glycoproteins E1 and E2, present at the surface of HCV particles. Non-structural (NS) proteins consist of NS1, NS2, NS3, NS4A, NS4B, NS5a, and NS5b and have a variable function in HCV RNA replication and particle assembly. Recent findings evidenced the capacity of HCV virus to modulate host cell factors to create a favorable environment for replication. Indeed, increasing evidence has indicated that the presence of HCV is significantly associated with aberrant miRNA expression in host cells, and HCV structural and non-structural proteins may be responsible for these alterations. In this review, we summarize the recent findings on the role of HCV structural and non-structural proteins in the modulation of host cell miRNAs, with a focus on the molecular mechanisms responsible for the cell re-programming involved in viral replication, immune system escape, as well as the oncogenic process. In this regard, structural and non-structural proteins have been shown to modulate the expression of several onco-miRNAs or tumor suppressor miRNAs.

Hepatocellular carcinoma, hepatitis C virus infection and miRNA involvement: Perspectives for new therapeutic approaches

“…The mechanisms that drive liver injury during HCV infection have not been fully elucidated. Several studies have attempted to understand the interactions between viral proteins and the cellular host machinery[ 93 ]. An important effort has been made to address and understand the complex interconnections between HCV infection and miRNAs, aimed at finding new therapeutic and diagnostic tools.…”

Biomarkers for the Detection and Management of Hepatocellular Carcinoma in Patients Treated with Direct-Acting Antivirals

“…Dysregulation induced by HCV involves also miRNAs [ 48 ]. In vitro studies showed that core and NS4B proteins can independently activate miR-27a and miR-27b expression, promoting lipogenesis and subsequently steatosis.…”

Role of Virus-Induced Host Cell Epigenetic Changes in Cancer

“…HCV does not seem to encode viral microRNA probably because of its cytoplasmic location, which deprives the virus from nuclear proteins, such as RNA polymerase II and Drosha, required for microRNA biogenesis. However, comparative microRNAome profiling of HBV-associated HCCs and HBV-negative HCCs, and of HepG2 hepatocytes stably transfected and full-length HCV genome and control cells demonstrated that HCV elicited changes in cellular miRNA expression [ 238 , 261 , 262 , 263 ]. MicroRNAs including miR-30c, miR-122, miR-124, miR-138, miR-152, and miR-203 were downregulated, whereas miR-21, miR-93, 193b, miR-196a, and miR-758 were upregulated.…”

“…Another mechanism by which the core protein affected microRNA levels was by suppressing the activity of Dicer, thereby interfering with the biogenesis of microRNAs [ 264 ]. The non-structural proteins NS3, NS4A, NS4B, and NS5A also affected the expression of cellular microRNAs that stimulate proliferation, cell survival, migration and invasion, and immune evasion [ 238 ]. The mechanisms by which these HCV proteins modify microRNA expression remains to be determined.…”