RKIP Regulates Differentiation-Related Features in Melanocytic Cells

Raf Kinase Inhibitor Protein (RKIP) has been extensively reported as an inhibitor of keysignaling pathways involved in the aggressive tumor phenotype and shows decreased expressionin several types of cancers. However, little is known about RKIP in melanoma or regarding its functionin normal cells. W...

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Autores: Penas Lago, Cristina, Apraiz García, Aintzane, Muñoa Hoyos, Iraia, Arroyo Berdugo, Yoana, Rasero, Javier, Ezcurra García Unzueta, Pilar Ariadna, Velasco, Verónica, Subirán Ciudad, Nerea, Bosserhoff, Anja K., Alonso Alegre, Santos, Asumendi Mallea, Aintzane, Boyano López, María Dolores
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universidad del País Vasco
Repositorio:Addi. Archivo Digital para la Docencia y la Investigación
OAI Identifier:oai:addi.ehu.eus:10810/44809
Acceso en línea:http://hdl.handle.net/10810/44809
Access Level:acceso abierto
Palabra clave:RKIP
melanocytes
melanoma
transcriptome analysis
cell motility
differentiation
biomarke
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spelling RKIP Regulates Differentiation-Related Features in Melanocytic CellsPenas Lago, CristinaApraiz García, AintzaneMuñoa Hoyos, IraiaArroyo Berdugo, YoanaRasero, JavierEzcurra García Unzueta, Pilar AriadnaVelasco, VerónicaSubirán Ciudad, NereaBosserhoff, Anja K.Alonso Alegre, SantosAsumendi Mallea, AintzaneBoyano López, María DoloresRKIPmelanocytesmelanomatranscriptome analysiscell motilitydifferentiationbiomarkeRaf Kinase Inhibitor Protein (RKIP) has been extensively reported as an inhibitor of keysignaling pathways involved in the aggressive tumor phenotype and shows decreased expressionin several types of cancers. However, little is known about RKIP in melanoma or regarding its functionin normal cells. We examined the role of RKIP in both primary melanocytes and malignant melanomacells and evaluated its diagnostic and prognostic value. IHC analysis revealed a significantly higherexpression of RKIP in nevi compared with early-stage (stage I–II, AJCC 8th) melanoma biopsies.Proliferation, wound healing, and collagen-coated transwell assays uncovered the implication ofRKIP on the motility but not on the proliferative capacity of melanoma cells as RKIP protein levelswere inversely correlated with the migration capacity of both primary and metastatic melanoma cellsbut did not alter other parameters. As shown by RNA sequencing, endogenous RKIP knockdownin primary melanocytes triggered the deregulation of cellular differentiation-related processes,including genes (i.e., ZEB1, THY-1) closely related to the EMT. Interestingly, NANOG was identifiedas a putative transcriptional regulator of many of the deregulated genes, and RKIP was able todecrease the activation of the NANOG promoter. As a whole, our data support the utility of RKIPas a diagnostic marker for early-stage melanomas. In addition, these findings indicate its participationin the maintenance of a differentiated state of melanocytic cells by modulating genes intimately linkedto the cellular motility and explain the progressive decrease of RKIP often described in tumors.This project was supported by grants from the Basque Government (KK2016-036 and KK2017-041 toM.D.B.), UPV/EHU (GIU17/066 to M.D.B.), H2020-ESCEL JTI (15/01 to M.D.B.) and MINECO (PCIN-2015-241 toM.D.B.). CP holds a predoctoral fellowship from the Basque GovernmentMDPI2020202020202020info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10810/44809reponame:Addi. Archivo Digital para la Docencia y la Investigacióninstname:Universidad del País VascoInglésinfo:eu-repo/grantAgreement/MINECO/PCIN-2015-241 to M.D.B./https://www.mdpi.com/2072-6694/12/6/1451/review_reportinfo:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/3.0/es/2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open accessarticle distributed under the terms and conditions of the Creative Commons Attribution(CC BY) license (http://creativecommons.org/licenses/by/4.0/).oai:addi.ehu.eus:10810/448092026-06-18T09:23:17Z
dc.title.none.fl_str_mv RKIP Regulates Differentiation-Related Features in Melanocytic Cells
title RKIP Regulates Differentiation-Related Features in Melanocytic Cells
spellingShingle RKIP Regulates Differentiation-Related Features in Melanocytic Cells
Penas Lago, Cristina
RKIP
melanocytes
melanoma
transcriptome analysis
cell motility
differentiation
biomarke
title_short RKIP Regulates Differentiation-Related Features in Melanocytic Cells
title_full RKIP Regulates Differentiation-Related Features in Melanocytic Cells
title_fullStr RKIP Regulates Differentiation-Related Features in Melanocytic Cells
title_full_unstemmed RKIP Regulates Differentiation-Related Features in Melanocytic Cells
title_sort RKIP Regulates Differentiation-Related Features in Melanocytic Cells
dc.creator.none.fl_str_mv Penas Lago, Cristina
Apraiz García, Aintzane
Muñoa Hoyos, Iraia
Arroyo Berdugo, Yoana
Rasero, Javier
Ezcurra García Unzueta, Pilar Ariadna
Velasco, Verónica
Subirán Ciudad, Nerea
Bosserhoff, Anja K.
Alonso Alegre, Santos
Asumendi Mallea, Aintzane
Boyano López, María Dolores
author Penas Lago, Cristina
author_facet Penas Lago, Cristina
Apraiz García, Aintzane
Muñoa Hoyos, Iraia
Arroyo Berdugo, Yoana
Rasero, Javier
Ezcurra García Unzueta, Pilar Ariadna
Velasco, Verónica
Subirán Ciudad, Nerea
Bosserhoff, Anja K.
Alonso Alegre, Santos
Asumendi Mallea, Aintzane
Boyano López, María Dolores
author_role author
author2 Apraiz García, Aintzane
Muñoa Hoyos, Iraia
Arroyo Berdugo, Yoana
Rasero, Javier
Ezcurra García Unzueta, Pilar Ariadna
Velasco, Verónica
Subirán Ciudad, Nerea
Bosserhoff, Anja K.
Alonso Alegre, Santos
Asumendi Mallea, Aintzane
Boyano López, María Dolores
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv RKIP
melanocytes
melanoma
transcriptome analysis
cell motility
differentiation
biomarke
topic RKIP
melanocytes
melanoma
transcriptome analysis
cell motility
differentiation
biomarke
description Raf Kinase Inhibitor Protein (RKIP) has been extensively reported as an inhibitor of keysignaling pathways involved in the aggressive tumor phenotype and shows decreased expressionin several types of cancers. However, little is known about RKIP in melanoma or regarding its functionin normal cells. We examined the role of RKIP in both primary melanocytes and malignant melanomacells and evaluated its diagnostic and prognostic value. IHC analysis revealed a significantly higherexpression of RKIP in nevi compared with early-stage (stage I–II, AJCC 8th) melanoma biopsies.Proliferation, wound healing, and collagen-coated transwell assays uncovered the implication ofRKIP on the motility but not on the proliferative capacity of melanoma cells as RKIP protein levelswere inversely correlated with the migration capacity of both primary and metastatic melanoma cellsbut did not alter other parameters. As shown by RNA sequencing, endogenous RKIP knockdownin primary melanocytes triggered the deregulation of cellular differentiation-related processes,including genes (i.e., ZEB1, THY-1) closely related to the EMT. Interestingly, NANOG was identifiedas a putative transcriptional regulator of many of the deregulated genes, and RKIP was able todecrease the activation of the NANOG promoter. As a whole, our data support the utility of RKIPas a diagnostic marker for early-stage melanomas. In addition, these findings indicate its participationin the maintenance of a differentiated state of melanocytic cells by modulating genes intimately linkedto the cellular motility and explain the progressive decrease of RKIP often described in tumors.
publishDate 2020
dc.date.none.fl_str_mv 2020
2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10810/44809
url http://hdl.handle.net/10810/44809
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/MINECO/PCIN-2015-241 to M.D.B./
https://www.mdpi.com/2072-6694/12/6/1451/review_report
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/3.0/es/
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:Addi. Archivo Digital para la Docencia y la Investigación
instname:Universidad del País Vasco
instname_str Universidad del País Vasco
reponame_str Addi. Archivo Digital para la Docencia y la Investigación
collection Addi. Archivo Digital para la Docencia y la Investigación
repository.name.fl_str_mv
repository.mail.fl_str_mv
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