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

Marie-Laure Plissonnier,David Durantel,Romain Parent,Andrea Paradisi,Shirit Einav,Jessica Cottarel,Fanny Lebossé,Mojgan Devouassoux-Shisheboran,Rosita Accardi,Thomas Lahlali,Melanie Beer,Maud Michelet,Fabien Zoulim,Grégory Neveu,Patrick Mehlen,Birke Bartosch,Sophie Clément

doi:10.1371/journal.pbio.1002421

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.

Highlights

Cancers triggered by microbial oncogenes account for approximately 16% of cancer occurrences [1]
We show that Hepatitis C virus (HCV) and Netrin-1 are mutual inducers—Netrin-1 expression is increased upon HCV infection and, in turn, the rise in Netrin-1 leads to an increase in the HCV particle infectivity
The effects on HCV infectivity involve the liver cancer-related epidermal growth factor receptor (EGFR), which is known to be a host receptor necessary for HCV entry and which we show is activated by Netrin-1

Summary

Introduction

Cancers triggered by microbial oncogenes account for approximately 16% of cancer occurrences [1]. An interesting advance in developmental biology and oncology in the last decade was the discovery of dependence receptors (DRs) [9,10,11,12,13], a class of receptors that auto-activate and trigger apoptosis in the absence of their ligands. Netrin-1 is a secreted protein that was initially identified as the canonical soluble partner of the uncoordinated receptor-5 (UNC5) DR family in the field of neuroembryogenesis It inactivates UNC5-mediated intrinsic signals, including cell death, unlike most ligands that exert positive pharmacology on their cognate receptors. As is the case for most viral infections, chronic hepatitis C bears an important inflammatory component, thought to strongly participate in the worsening of the liver structure and function, which could result in cancer promotion within hepatocytic compartments

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Conclusion