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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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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