RT Journal Article
SR Electronic
T1 miR-135a-5p-mediated downregulation of protein tyrosine phosphatase receptor delta is a candidate driver of HCV-associated hepatocarcinogenesis
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 953
OP 962
DO 10.1136/gutjnl-2016-312270
VO 67
IS 5
A1 Nicolaas Van Renne
A1 Armando Andres Roca Suarez
A1 Francois H T Duong
A1 Claire Gondeau
A1 Diego Calabrese
A1 Nelly Fontaine
A1 Amina Ababsa
A1 Simonetta Bandiera
A1 Tom Croonenborghs
A1 Nathalie Pochet
A1 Vito De Blasi
A1 Patrick Pessaux
A1 Tullio Piardi
A1 Daniele Sommacale
A1 Atsushi Ono
A1 Kazuaki Chayama
A1 Masashi Fujita
A1 Hidewaki Nakagawa
A1 Yujin Hoshida
A1 Mirjam B Zeisel
A1 Markus H Heim
A1 Thomas F Baumert
A1 Joachim Lupberger
YR 2018
UL http://gut.bmj.com/content/67/5/953.abstract
AB 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.