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.

• Authors: Marie-Laure Plissonnier, Thomas Lahlali, Maud Michelet, Fanny Lebossé, Jessica Cottarel, Melanie Beer, Grégory Neveu, David Durantel, Birke Bartosch, Rosita Accardi, Sophie Clément, Andrea Paradisi, Mojgan Devouassoux-Shisheboran, Shirit Einav, Patrick Mehlen, Fabien Zoulim, Romain Parent
• Journal: PLoS biology (PLoS Biol) Vol. 14 Issue 3 Pg. e1002421 (Mar 2016) ISSN: 1545-7885 [Electronic] United States
• PMID: 27031829 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Autoantigens
• NTN1 protein, human
• Nerve Growth Factors
• Ribonucleoproteins
• Tumor Suppressor Proteins
• Viral Nonstructural Proteins
• Netrin-1
• EGFR protein, human
• ErbB Receptors
• NS-5 protein, hepatitis C virus

Topics

• Autoantigens (metabolism)
• Carcinoma, Hepatocellular (etiology, metabolism)
• Cell Line
• Cell Transformation, Neoplastic
• ErbB Receptors (metabolism)
• Hepatitis C (complications, metabolism, virology)
• Humans
• Liver Cirrhosis (metabolism, virology)
• Liver Neoplasms (etiology, metabolism)
• Nerve Growth Factors (metabolism)
• Netrin-1
• Ribonucleoproteins (metabolism)
• Tumor Suppressor Proteins (metabolism)
• Up-Regulation
• Viral Nonstructural Proteins (metabolism)
• Virus Internalization
• SS-B Antigen