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Original article
miR-135a-5p-mediated downregulation of protein tyrosine phosphatase receptor delta is a candidate driver of HCV-associated hepatocarcinogenesis
  1. Nicolaas Van Renne1,2,
  2. Armando Andres Roca Suarez1,2,
  3. Francois H T Duong3,
  4. Claire Gondeau4,5,
  5. Diego Calabrese3,
  6. Nelly Fontaine1,2,
  7. Amina Ababsa1,2,
  8. Simonetta Bandiera1,2,
  9. Tom Croonenborghs6,7,
  10. Nathalie Pochet6,7,
  11. Vito De Blasi1,2,8,
  12. Patrick Pessaux1,2,8,
  13. Tullio Piardi9,
  14. Daniele Sommacale9,
  15. Atsushi Ono10,11,
  16. Kazuaki Chayama11,12,13,
  17. Masashi Fujita14,
  18. Hidewaki Nakagawa14,
  19. Yujin Hoshida10,
  20. Mirjam B Zeisel1,2,
  21. Markus H Heim3,
  22. Thomas F Baumert1,2,8,
  23. Joachim Lupberger1,2
  1. 1Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
  2. 2Université de Strasbourg, Strasbourg, France
  3. 3Department of Biomedicine, Hepatology Laboratory, University of Basel, Basel, Switzerland
  4. 4Inserm, U1183, Institut de Médecine Régénératrice et Biothérapie, Université de Montpellier, Montpellier, France
  5. 5Département d'Hépato-gastro-entérologie A, Hôpital Saint Eloi, CHU Montpellier, Montpellier, France
  6. 6The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA
  7. 7Program in Translational NeuroPsychiatric Genomics, Brigham and Women's Hospital, Harvard Medical School, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA
  8. 8Pôle Hépato-digestif, Institut Hospitalo-universitaire, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
  9. 9Department of General, Digestive and Endocrine Surgery, Hôpital Robert Debré, Centre Hospitalier Universitaire de Reims, Université de Reims Champagne-Ardenne, Reims, France
  10. 10Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
  11. 11Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
  12. 12Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan
  13. 13Liver Research Project Center, Hiroshima University, Hiroshima, Japan
  14. 14Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan
  1. Correspondence to Dr Joachim Lupberger, Inserm U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 3, rue Koeberlé, Strasbourg 67000, France; joachim.lupberger{at}unistra.fr

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.

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Footnotes

  • Contributors JL initiated and supervised the study. JL and TFB obtained funding. NVR, AARS, FHTD, JL, CG, DC, NF and AA designed and conducted experiments and analysed data. TP, DS, VD, PP and MHH provided patient liver tissue and corresponding clinical data. AO, KC, MF, HN and YH provided gene expression data from patient cohorts and performed patient survival analysis. SB and MBZ analysed HCV-induced miRNA expression in Huh7.5.1 cells and designed miRNA reporter assays. TC, NP and NVR performed GSEA analysis. NVR and JL wrote the manuscript. MHH, YH, MBZ and TFB critically reviewed the manuscript.

  • Funding This work was supported by grants from the Wilhelm Sander-Stiftung (Förderantrag 2010.023.1 to TFB), the European Union (Interreg IV-Rhin Supérieur-FEDER-Hepato-Regio-Net to TFB and MBZ; ERC-AdG-2014 HEPCIR to TFB; EU H2020 HEPCAR to TFB), the French Cancer Agency (ARC IHU201301187 to TFB), the University of Strasbourg (IdEx, Projet Attractivité 2014, ANR, to JL) and from the French ANRS (ECTZ4236, ECTZ4446 to JL and AARS). NVR was funded by an IdEx fellowship from the University of Strasbourg (IdEx, Contrat Doctoral 2012, ANR, to MBZ and TFB). This work has been published under the framework of the LABEX ANR-10-LAB-28 and benefits from a funding from the state managed by the French National Research Agency as part of the investments for the future programme.

  • Competing interests None declared.

  • Ethics approval Ethics Committees of the University Hospital of Basel (Switzerland), the Centre Hospitalier Universitaire de Reims (France) and the Hôpitaux Universitaires de Strasbourg (France).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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