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



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.



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.



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.
Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.
Nicolaas
0000-0002-3053-8835
N
Van Renne
Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.
Armando Andres
0000-0002-2620-4461
AA
Roca Suarez
Department of Biomedicine, Hepatology Laboratory, University of Basel, Basel, Switzerland.
Francois H T
FHT
Duong
Inserm, U1183, Institut de Médecine Régénératrice et Biothérapie, Université de Montpellier, Montpellier, France.|Département d'Hépato-gastro-entérologie A, Hôpital Saint Eloi, CHU Montpellier, Montpellier, France.
Claire
C
Gondeau
Department of Biomedicine, Hepatology Laboratory, University of Basel, Basel, Switzerland.
Diego
0000-0002-0259-8611
D
Calabrese
Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.
Nelly
N
Fontaine
Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.
Amina
A
Ababsa
Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.
Simonetta
S
Bandiera
The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA.|Program in Translational NeuroPsychiatric Genomics, Brigham and Women's Hospital, Harvard Medical School, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA.
Tom
T
Croonenborghs
The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA.|Program in Translational NeuroPsychiatric Genomics, Brigham and Women's Hospital, Harvard Medical School, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA.
Nathalie
N
Pochet
Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.|Pôle Hépato-digestif, Institut Hospitalo-universitaire, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Vito
V
De Blasi
Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.|Pôle Hépato-digestif, Institut Hospitalo-universitaire, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Patrick
0000-0001-5635-7437
P
Pessaux
Department of General, Digestive and Endocrine Surgery, Hôpital Robert Debré, Centre Hospitalier Universitaire de Reims, Université de Reims Champagne-Ardenne, Reims, France.
Tullio
T
Piardi
Department of General, Digestive and Endocrine Surgery, Hôpital Robert Debré, Centre Hospitalier Universitaire de Reims, Université de Reims Champagne-Ardenne, Reims, France.
Daniele
D
Sommacale
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
Atsushi
A
Ono
Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.|Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan.|Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
Kazuaki
K
Chayama
Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
Masashi
M
Fujita
Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
Hidewaki
H
Nakagawa
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Yujin
Y
Hoshida
Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.
Mirjam B
MB
Zeisel
Department of Biomedicine, Hepatology Laboratory, University of Basel, Basel, Switzerland.
Markus H
MH
Heim
Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.|Pôle Hépato-digestif, Institut Hospitalo-universitaire, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Thomas F
TF
Baumert
Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France.|Université de Strasbourg, Strasbourg, France.
Joachim
0000-0003-3996-3907
J
Lupberger
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D063646:Carcinogenesis / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000821:virology; D015536:Down-Regulation; D005260:Female; D016174:Hepacivirus / Q000472:pathogenicity*; D006526:Hepatitis C / Q000150:complications*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000821:virology; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
C544965:MIRN135 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C090899:PTPRD protein, human; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2
HCV; HEPATOCELLULAR CARCINOMA; SIGNALING