Epidermal Growth Factor Receptor-Dependent Mutual Amplification between Netrin-1 and the Hepatitis C Virus

Abstract

Hepatitis C virus (HCV) is an oncogenic virus associated with the onset of hepatocellular carcinoma (HCC). The present study investigated the possible link between HCV infection and Netrin-1, a ligand for dependence receptors that sustains tumorigenesis, in particular in inflammation-associated tumors. We show that Netrin-1 expression is significantly elevated in HCV+ liver biopsies compared to hepatitis B virus (HBV+) and uninfected samples. Furthermore, Netrin-1 was upregulated in all histological stages of HCV+ hepatic lesions, from minimal liver fibrosis to cirrhosis and HCC, compared to histologically matched HCV- tissues. Both cirrhosis and HCV contributed to the induction of Netrin-1 expression, whereas anti-HCV treatment resulted in a reduction of Netrin-1 expression. In vitro, HCV increased the level and translation of Netrin-1 in a NS5A-La-related protein 1 (LARP1)-dependent fashion. Knockdown and forced expression experiments identified the receptor uncoordinated receptor-5 (UNC5A) as an antagonist of the Netrin-1 signal, though it did not affect the death of HCV-infected cells. Netrin-1 enhanced infectivity of HCV particles and promoted viral entry by increasing the activation and decreasing the recycling of the epidermal growth factor receptor (EGFR), a protein that is dysregulated in HCC. Netrin-1 and HCV are, therefore, reciprocal inducers in vitro and in patients, as seen from the increase in viral morphogenesis and viral entry, both phenomena converging toward an increase in the level of infectivity of HCV virions. This functional association involving a cancer-related virus and Netrin-1 argues for evaluating the implication of UNC5 receptor ligands in other oncogenic microbial species.

Hepatitis C Virus and Hepatocellular Carcinoma: When the Host Loses Its Grip

“…In the early stages of the viral life cycle, HCV binding to its entry receptor complex, i.e., CD81 and claudin-1 (CLDN1), induces EGFR phosphorylation [54] and downstream signaling [55], thereby facilitating viral particle internalization. EGFR activity is prolonged by the NS5A-mediated alteration of EGFR trafficking [56] and by stimulated Netrin-1 expression, which impedes EGFR recycling [57]. Moreover, HCV replication itself promotes the expression of the receptor ligand EGF [58].…”

Dependence receptor UNC5A restricts luminal to basal breast cancer plasticity and metastasis

“…Second, sh-UNC5A cells showed luminal/basal hybrid phenotype, and EGFR activation is common in cells with basal phenotype [ 48 ]. Third, a recent study showed that NTN1, in the absence of UNC5A, increases EGFR at the post-translational level [ 49 ]. We first measured EGFR levels in sh-Control and UNC5A knockdown cells.…”

Inhibition of EGFR Signaling Protects from Mucormycosis

“…In addition, many pathogens, including viruses, bacteria, and fungi, seem to have evolved the ability to exploit EGFR signaling to gain entry into host cells ( 33 ), and the mechanism of EGFR activation across these pathogenic microbes varies. For example, in the context of viral infection, hepatitis C virus increases signaling by disrupting EGFR recycling to enhance its surface expression ( 43 , 44 ). In contrast, the Campylobacter jejuni bacterium induces lipid raft formation, resulting in clustering and subsequent activation of EGFR ( 45 ), while meningitic Escherichia coli activates EGFR signaling by increasing sphingosine 1-phosphate (S1P 2 )-dependent release of heparin-binding ligand-like epidermal growth factor (HB-EGF) ( 35 ).…”