The netrin-1/UNC5 axis in chronic liver disease associated with liver cancer
Netrin-1 is a secreted molecule implicated in neural development. It has also been shown to be involved in the pathogenesis and treatment resistance of a substantial range of cancer types.
However, no study has been adressing the role of netrin-1 in the liver field for years. We have previously implemented several studies aiming at defining the role of the netrin-1 / UNC5A axis in chronic liver disease, using the HCV and the UPR models.
We have shown that:
– Netrin-1 and HCV are 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, in an EGFR-dependent manner. 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.
– The UNC5A dependence receptor counteracts HCV persistence through regulation of autophagy in a DAPK-dependent manner, and is dramatically decreased in all instances in HCC samples, and specifically by HCV in cirrhosis.
– Unlike several structurally related oncogenic transcripts (l-myc, c-myc, c-myb), netrin-1 messenger RNA was selected for translation during UPR both in human hepatocytes and in mice livers. Depletion of netrin-1 during UPR induces apoptosis, leading to cell death through an uncoordinated phenotype-5A/C-mediated involvement of protein phosphatase 2A and death-associated protein kinase 1 in vitro and in netrin transgenic mice. IRES-driven netrin-1 translation leads to the inhibition of UNC5A/DAPK1-mediated apoptosis in the hepatic context during UPR, a hallmark of chronic liver disease.
Our objectives are to define:
– The implication of netrin-1 in liver inflammation (current Labex funded PhD student)
– The implication of netrin-1 in HCC onset (current ANRS funded program involving also a research assistant)
Since netrin-1 upregulation spans a wide spectrum of liver diseases (Plos Biol 2016), such programs represent an important part of the Pathology program of the Zoulim Team, which lies besides the HBV basic and the HBV immunopathology program of the team.
1: Plissonnier ML, Lahlali T, Raab M, Michelet M, Romero-López C, Rivoire M, Strebhardt K, Durantel D, Levrero M, Mehlen P, Zoulim F, Parent R. Reciprocal antagonism between the netrin-1 receptor uncoordinated-phenotype-5A (UNC5A) and the hepatitis C virus. Oncogene. 2017 Aug 7. doi: 10.1038/onc.2017.271. [Epub ahead of print] PubMed PMID: 28783179.
2: Lahlali T, Plissonnier ML, Romero-López C, Michelet M, Ducarouge B, Berzal-Herranz A, Zoulim F, Mehlen P, Parent R. Netrin-1 Protects Hepatocytes Against Cell Death Through Sustained Translation During the Unfolded Protein Response. Cell Mol Gastroenterol Hepatol. 2016 Jan 9;2(3):281-301.e9. doi: 10.1016/j.jcmgh.2015.12.011. eCollection 2016 May. PubMed PMID: 28174720; PubMed Central PMCID: PMC5042567.
3: Plissonnier ML, Lahlali T, Michelet M, Lebossé F, Cottarel J, Beer M, Neveu G, Durantel D, Bartosch B, Accardi R, Clément S, Paradisi A, Devouassoux-Shisheboran
M, Einav S, Mehlen P, Zoulim F, Parent R. Epidermal Growth Factor Receptor-Dependent Mutual Amplification between Netrin-1 and the Hepatitis C Virus. PLoS Biol. 2016 Mar 31;14(3):e1002421. doi: 10.1371/journal.pbio.1002421. eCollection 2016 Mar. PubMed PMID: 27031829; PubMed Central PMCID: PMC4816328.
4: Plissonnier ML, Lahlali T, Mehlen P, Parent R. [Hepatitis C, EGFR, cirrhosis and netrin-1: potential implications for HCC onset]. Med Sci (Paris). 2016 Jun-Jul;32(6-7):566-8. doi: 10.1051/medsci/20163206013. Epub 2016 Jul 12. French. PubMed PMID: 27406760.
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