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

Nicolaas Van Renne, Armando Andres Roca Suarez, Francois H.T. Duong, Claire Gondeau, Diego Calabrese, Nelly Fontaine, Amina Ababsa, Simonetta Bandiera, Tom Croonenborghs, Nathalie Pochet, Vito De Blasi, Patrick Pessaux, Tullio Piardi, Daniele Sommacale, Atsushi Ono, Kazuaki Chayama, Masashi Fujita, Hidewaki Nakagawa, Yujin Hoshida, Mirjam B. ZeiselMarkus H. Heim, Thomas F. Baumert, Joachim Lupberger

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)953-962
Number of pages10
JournalGut
Volume67
Issue number5
DOIs
StatePublished - May 1 2018

Keywords

  • HCV
  • HEPATOCELLULAR CARCINOMA
  • SIGNALING

ASJC Scopus subject areas

  • Gastroenterology

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    Van Renne, N., Roca Suarez, A. A., Duong, F. H. T., Gondeau, C., Calabrese, D., Fontaine, N., Ababsa, A., Bandiera, S., Croonenborghs, T., Pochet, N., De Blasi, V., Pessaux, P., Piardi, T., Sommacale, D., Ono, A., Chayama, K., Fujita, M., Nakagawa, H., Hoshida, Y., ... Lupberger, J. (2018). MiR-135a-5p-mediated downregulation of protein tyrosine phosphatase receptor delta is a candidate driver of HCV-associated hepatocarcinogenesis. Gut, 67(5), 953-962. https://doi.org/10.1136/gutjnl-2016-312270