miR-135a-5p-mediated downregulation of protein tyrosine phosphatase receptor delta is a candidate driver of HCV-associated hepatocarcinogenesis

Nicolaas van Renne (1) , Armando Andres Roca Suarez (1) , Francois Duong (2) , Claire Gondeau (3, 4) , Diego Calabrese (2) , Nelly Fontaine (1) , Amina Ababsa (1) , Simonetta Bandiera (1) , Tom Croonenborghs (5) , Nathalie Pochet (5) , Vito de Blasi (6, 1, 7) , Patrick Pessaux (6, 1, 7) , Tullio Piardi (8, 9) , Daniele Sommacale (8, 9) , Atsushi Ono (10, 11) , Kazuaki Chayama (11, 12) , Masashi Fujita (13) , Hidewaki Nakagawa (13) , Yujin Hoshida (10) , Mirjam B. Zeisel (14) , Markus Heim (15) , Thomas F. Baumert (14, 6, 7) , Joachim Lupberger (14)

1 IVH - Institut de Recherche sur les Maladies Virales et Hépatiques
2 University Hospital Basel [Basel]
3 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
4 Hôpital Saint Eloi [CHU Montpellier]
5 Harvard-MIT Division of Health Sciences and Technology [Cambridge]
6 IHU Strasbourg - L'Institut hospitalo-universitaire de Strasbourg
7 HUS - Les Hôpitaux Universitaires de Strasbourg
8 URCA - Université de Reims Champagne-Ardenne
9 Hôpital Robert Debré
10 MSSM - Icahn School of Medicine at Mount Sinai [New York]
11 Hiroshima University
12 RIKEN - RIKEN - Institute of Physical and Chemical Research [Japon]
13 RIKEN IMS - RIKEN Center for Integrative Medical Sciences [Yokohama]
14 ITM - Institute for Translational Medicine and Liver Disease
15 Unibas - Université de Bâle = University of Basel = Basel Universität

Background and aims: HCV infection is a leading risk factor of hepatocellular carcinoma (HCC). However, even after viral clearance, HCC risk remains elevated. HCV perturbs host cell signalling to maintain infection, and derailed signalling circuitry is a key driver of carcinogenesis. Since protein phosphatases are regulators of signalling events, we aimed to identify phosphatases that respond to HCV infection with relevance for hepatocarcinogenesis. Methods: We assessed mRNA and microRNA (miRNA) expression profiles in primary human hepatocytes, liver biopsies and resections of patients with HCC, and analysed microarray and RNA-seq data from paired liver biopsies of patients with HCC. We revealed changes in transcriptional networks through gene set enrichment analysis and correlated phosphatase expression levels to patient survival and tumour recurrence. Results: We demonstrate that tumour suppressor protein tyrosine phosphatase receptor delta (PTPRD) is impaired by HCV infection in vivo and in HCC lesions of paired liver biopsies independent from tissue inflammation or fibrosis. In liver tissue adjacent to tumour, high PTPRD levels are associated with a dampened transcriptional activity of STAT3, an increase of patient survival from HCC and reduced tumour recurrence after surgical resection. We identified miR-135a-5p as a mechanistic regulator of hepatic PTPRD expression in patients with HCV. Conclusions: We previously demonstrated that STAT3 is required for HCV infection. We conclude that HCV promotes a STAT3 transcriptional programme in the liver of patients by suppressing its regulator PTPRD via upregulation of miR-135a-5p. Our results show the existence of a perturbed PTPRD-STAT3 axis potentially driving malignant progression of HCV-associated liver disease.

Mots clés: HCV; HEPATOCELLULAR CARCINOMA; SIGNALING

Domaines: Sciences du Vivant [q-bio]

Nicolaas van Renne, Armando Andres Roca Suarez, Francois Duong, Claire Gondeau, Diego Calabrese, et al.. miR-135a-5p-mediated downregulation of protein tyrosine phosphatase receptor delta is a candidate driver of HCV-associated hepatocarcinogenesis. Gut, 2018, 67 (5), pp.953 - 962. ⟨10.1136/gutjnl-2016-312270⟩. ⟨hal-01837106⟩