Merkel Cell Polyomavirus T Antigens Induce Merkel Cell-Like Differentiation in GLI1-Expressing Epithelial Cells
Merkel cell carcinoma (MCC) is an aggressive skin cancer frequently caused by the Merkel cell polyomavirus (MCPyV). It is still under discussion, in which cells viral integration and MCC development occurs. Recently, we demonstrated that a virus-positive MCC derived from a trichoblastoma, an epithel...
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doaj-4e6cbac6a8884dc9911b3fae432fc75e2020-11-25T02:49:17ZengMDPI AGCancers2072-66942020-07-01121989198910.3390/cancers12071989Merkel Cell Polyomavirus T Antigens Induce Merkel Cell-Like Differentiation in GLI1-Expressing Epithelial CellsThibault Kervarrec0Mahtab Samimi1Sonja Hesbacher2Patricia Berthon3Marion Wobser4Aurélie Sallot5Bhavishya Sarma6Sophie Schweinitzer7Théo Gandon8Christophe Destrieux9Côme Pasqualin10Serge Guyétant11Antoine Touzé12Roland Houben13David Schrama14Department of Pathology, Université de Tours, CHU de Tours, Avenue de la République, 37170 Chambray-les-Tours, France“Biologie des Infections à Polyomavirus” Team, UMR INRA ISP 1282, Université de Tours, 31 Avenue Monge, 37200 Tours, FranceDepartment of Dermatology, Venereology and Allergology, University Hospital Würzburg, Josef-Schneider-Straße 2, 97080 Würzburg, Germany“Biologie des Infections à Polyomavirus” Team, UMR INRA ISP 1282, Université de Tours, 31 Avenue Monge, 37200 Tours, FranceDepartment of Dermatology, Venereology and Allergology, University Hospital Würzburg, Josef-Schneider-Straße 2, 97080 Würzburg, GermanyPlastic Surgery Department, Université de Tours, CHU de Tours, Avenue de la République, 37170 Chambray-les-Tours, FranceDepartment of Dermatology, Venereology and Allergology, University Hospital Würzburg, Josef-Schneider-Straße 2, 97080 Würzburg, GermanyDepartment of Dermatology, Venereology and Allergology, University Hospital Würzburg, Josef-Schneider-Straße 2, 97080 Würzburg, Germany“Biologie des Infections à Polyomavirus” Team, UMR INRA ISP 1282, Université de Tours, 31 Avenue Monge, 37200 Tours, FranceNeurosurgery Department, UMR 1253, i Brain, Université De Tours, CHU de Tours, Boulevard Tonnelé, 37044 Tours, FranceCNRS ERL 7368, Signalisation et Transports Ioniques Membranaires, Equipe Transferts Ioniques et Rythmicité Cardiaque, Groupe Physiologie des Cellules Cardiaques et Vasculaires, Université de Tours, 31 Avenue Monge, 37200 Tours, FranceDepartment of Pathology, Université de Tours, CHU de Tours, Avenue de la République, 37170 Chambray-les-Tours, France“Biologie des Infections à Polyomavirus” Team, UMR INRA ISP 1282, Université de Tours, 31 Avenue Monge, 37200 Tours, FranceDepartment of Dermatology, Venereology and Allergology, University Hospital Würzburg, Josef-Schneider-Straße 2, 97080 Würzburg, GermanyDepartment of Dermatology, Venereology and Allergology, University Hospital Würzburg, Josef-Schneider-Straße 2, 97080 Würzburg, GermanyMerkel cell carcinoma (MCC) is an aggressive skin cancer frequently caused by the Merkel cell polyomavirus (MCPyV). It is still under discussion, in which cells viral integration and MCC development occurs. Recently, we demonstrated that a virus-positive MCC derived from a trichoblastoma, an epithelial neoplasia bearing Merkel cell (MC) differentiation potential. Accordingly, we hypothesized that MC progenitors may represent an origin of MCPyV-positive MCC. To sustain this hypothesis, phenotypic comparison of trichoblastomas and physiologic human MC progenitors was conducted revealing GLI family zinc finger 1 (GLI1), Keratin 17 (KRT 17), and SRY-box transcription factor 9 (SOX9) expressions in both subsets. Furthermore, GLI1 expression in keratinocytes induced transcription of the MC marker SOX2 supporting a role of GLI1 in human MC differentiation. To assess a possible contribution of the MCPyV T antigens (TA) to the development of an MC-like phenotype, human keratinocytes were transduced with TA. While this led only to induction of KRT8, an early MC marker, combined GLI1 and TA expression gave rise to a more advanced MC phenotype with SOX2, KRT8, and KRT20 expression. Finally, we demonstrated MCPyV-large T antigens’ capacity to inhibit the degradation of the MC master regulator Atonal bHLH transcription factor 1 (ATOH1). In conclusion, our report suggests that MCPyV TA contribute to the acquisition of an MC-like phenotype in epithelial cells.https://www.mdpi.com/2072-6694/12/7/1989Merkel cell carcinomahistogenesispolyomavirusATOH1GLI1sonic hedgehog |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Thibault Kervarrec Mahtab Samimi Sonja Hesbacher Patricia Berthon Marion Wobser Aurélie Sallot Bhavishya Sarma Sophie Schweinitzer Théo Gandon Christophe Destrieux Côme Pasqualin Serge Guyétant Antoine Touzé Roland Houben David Schrama |
spellingShingle |
Thibault Kervarrec Mahtab Samimi Sonja Hesbacher Patricia Berthon Marion Wobser Aurélie Sallot Bhavishya Sarma Sophie Schweinitzer Théo Gandon Christophe Destrieux Côme Pasqualin Serge Guyétant Antoine Touzé Roland Houben David Schrama Merkel Cell Polyomavirus T Antigens Induce Merkel Cell-Like Differentiation in GLI1-Expressing Epithelial Cells Cancers Merkel cell carcinoma histogenesis polyomavirus ATOH1 GLI1 sonic hedgehog |
author_facet |
Thibault Kervarrec Mahtab Samimi Sonja Hesbacher Patricia Berthon Marion Wobser Aurélie Sallot Bhavishya Sarma Sophie Schweinitzer Théo Gandon Christophe Destrieux Côme Pasqualin Serge Guyétant Antoine Touzé Roland Houben David Schrama |
author_sort |
Thibault Kervarrec |
title |
Merkel Cell Polyomavirus T Antigens Induce Merkel Cell-Like Differentiation in GLI1-Expressing Epithelial Cells |
title_short |
Merkel Cell Polyomavirus T Antigens Induce Merkel Cell-Like Differentiation in GLI1-Expressing Epithelial Cells |
title_full |
Merkel Cell Polyomavirus T Antigens Induce Merkel Cell-Like Differentiation in GLI1-Expressing Epithelial Cells |
title_fullStr |
Merkel Cell Polyomavirus T Antigens Induce Merkel Cell-Like Differentiation in GLI1-Expressing Epithelial Cells |
title_full_unstemmed |
Merkel Cell Polyomavirus T Antigens Induce Merkel Cell-Like Differentiation in GLI1-Expressing Epithelial Cells |
title_sort |
merkel cell polyomavirus t antigens induce merkel cell-like differentiation in gli1-expressing epithelial cells |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2020-07-01 |
description |
Merkel cell carcinoma (MCC) is an aggressive skin cancer frequently caused by the Merkel cell polyomavirus (MCPyV). It is still under discussion, in which cells viral integration and MCC development occurs. Recently, we demonstrated that a virus-positive MCC derived from a trichoblastoma, an epithelial neoplasia bearing Merkel cell (MC) differentiation potential. Accordingly, we hypothesized that MC progenitors may represent an origin of MCPyV-positive MCC. To sustain this hypothesis, phenotypic comparison of trichoblastomas and physiologic human MC progenitors was conducted revealing GLI family zinc finger 1 (GLI1), Keratin 17 (KRT 17), and SRY-box transcription factor 9 (SOX9) expressions in both subsets. Furthermore, GLI1 expression in keratinocytes induced transcription of the MC marker SOX2 supporting a role of GLI1 in human MC differentiation. To assess a possible contribution of the MCPyV T antigens (TA) to the development of an MC-like phenotype, human keratinocytes were transduced with TA. While this led only to induction of KRT8, an early MC marker, combined GLI1 and TA expression gave rise to a more advanced MC phenotype with SOX2, KRT8, and KRT20 expression. Finally, we demonstrated MCPyV-large T antigens’ capacity to inhibit the degradation of the MC master regulator Atonal bHLH transcription factor 1 (ATOH1). In conclusion, our report suggests that MCPyV TA contribute to the acquisition of an MC-like phenotype in epithelial cells. |
topic |
Merkel cell carcinoma histogenesis polyomavirus ATOH1 GLI1 sonic hedgehog |
url |
https://www.mdpi.com/2072-6694/12/7/1989 |
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