Dioxin receptor regulates aldehyde dehydrogenase to block melanoma tumorigenesis and metastasis

[Background] The dioxin (AhR) receptor can have oncogenic or tumor suppressor activities depending on the phenotype of the target cell. We have shown that AhR knockdown promotes melanoma primary tumorigenesis and lung metastasis in the mouse and that human metastatic melanomas had reduced AhR levels...

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Autores: Contador-Troca, María, Rodríguez, María Isabel, Oliver, Francisco Javier, Fernández-Salguero, Pedro M.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2015
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/122573
Acceso en línea:http://hdl.handle.net/10261/122573
Access Level:acceso abierto
Palabra clave:Dioxin receptor
Aldehyde dehydrogenase
Tumorigenesis
Lung metastasis
Cancer stem cells
Invasion
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spelling Dioxin receptor regulates aldehyde dehydrogenase to block melanoma tumorigenesis and metastasisContador-Troca, MaríaRodríguez, María IsabelOliver, Francisco JavierFernández-Salguero, Pedro M.Dioxin receptorAldehyde dehydrogenaseTumorigenesisLung metastasisCancer stem cellsInvasion[Background] The dioxin (AhR) receptor can have oncogenic or tumor suppressor activities depending on the phenotype of the target cell. We have shown that AhR knockdown promotes melanoma primary tumorigenesis and lung metastasis in the mouse and that human metastatic melanomas had reduced AhR levels with respect to benign nevi.[Methods] Mouse melanoma B16F10 cells were engineered by retroviral transduction to stably downregulate AhR expression, Aldh1a1 expression or both. They were characterized for Aldh1a1 activity, stem cell markers and migration and invasion in vitro. Their tumorigenicity in vivo was analyzed using xenografts and lung metastasis assays as well as in vivo imaging.[Results] Depletion of aldehyde dehydrogenase 1a1 (Aldh1a1) impairs the pro-tumorigenic and pro-metastatic advantage of melanoma cells lacking AhR expression (sh-AhR). Thus, Aldh1a1 knockdown in sh-AhR cells (sh-AhR + sh-Aldh1a1) diminished their migration and invasion potentials and blocked tumor growth and metastasis to the lungs in immunocompetent AhR+/+ recipient mice. However, Aldh1a1 downmodulation in AhR-expressing B16F10 cells did not significantly affect tumor growth in vivo. Aldh1a1 knockdown reduced the high levels of CD133 + /CD29 + /CD44 + cells, melanosphere size and the expression of the pluripotency marker Sox2 in sh-AhR cells. Interestingly, Sox2 increased Aldh1a1 expression in sh-AhR but not in sh-AhR + sh-Aldh1a1 cells, suggesting that Aldh1a1 and Sox2 may be co-regulated in melanoma cells. In vivo imaging revealed that mice inoculated with AhR + Aldh1a1 knockdown cells had reduced tumor burden and enhanced survival than those receiving Aldh1a1-expressing sh-AhR cells.[Conclusions] Aldh1a1 overactivation in an AhR-deficient background enhances melanoma progression. Since AhR may antagonize the protumoral effects of Aldh1a1, the AhR low -Aldh1a1 high phenotype could be indicative of bad outcome in melanoma.This work was supported by grants to P.M.F-S. from the Spanish Ministry of Economy and Competitiveness (BFU2011-22678 and SAF2014-51813-R) and from the Gobierno de Extremadura (GR10008) and to J.M.M. from the Agencia Extremeña de Cooperación Internacional para el Desarrollo (AEXCID-13IA002, Gobierno de Extremadura). Research at P.M.F-S and F.J.O. laboratories has been also funded by the Red Temática de Investigación Cooperativa en Cáncer (RTICC), Fondo de Investigaciones Sanitarias (FIS), Carlos III Institute, Spanish Ministry of Health (RD12/0036/0032 and RD12/0036/0026, respectively). M.C.T. was a F.P.I. fellow from the Spanish Ministry of Education and Sciences. All Spanish funding is co-sponsored by the European Union FEDER program. The support and help of the Servicio de Técnicas Aplicadas a las Biociencia (STAB) of the Universidad de Extremadura is greatly acknowledged.Peer reviewedBioMed CentralMinisterio de Economía y Competitividad (España)Junta de ExtremaduraAgencia Extremeña de Cooperación Internacional para el DesarrolloMinisterio de Sanidad, Servicios Sociales e Igualdad (España)Red Temática de Investigación Cooperativa en Cáncer (España)Ministerio de Educación y Ciencia (España)Instituto de Salud Carlos IIIUniversidad de ExtremaduraEuropean CommissionConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]201520152015info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/122573reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.1186/s12943-015-0419-9Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1225732026-05-22T06:33:51Z
dc.title.none.fl_str_mv Dioxin receptor regulates aldehyde dehydrogenase to block melanoma tumorigenesis and metastasis
title Dioxin receptor regulates aldehyde dehydrogenase to block melanoma tumorigenesis and metastasis
spellingShingle Dioxin receptor regulates aldehyde dehydrogenase to block melanoma tumorigenesis and metastasis
Contador-Troca, María
Dioxin receptor
Aldehyde dehydrogenase
Tumorigenesis
Lung metastasis
Cancer stem cells
Invasion
title_short Dioxin receptor regulates aldehyde dehydrogenase to block melanoma tumorigenesis and metastasis
title_full Dioxin receptor regulates aldehyde dehydrogenase to block melanoma tumorigenesis and metastasis
title_fullStr Dioxin receptor regulates aldehyde dehydrogenase to block melanoma tumorigenesis and metastasis
title_full_unstemmed Dioxin receptor regulates aldehyde dehydrogenase to block melanoma tumorigenesis and metastasis
title_sort Dioxin receptor regulates aldehyde dehydrogenase to block melanoma tumorigenesis and metastasis
dc.creator.none.fl_str_mv Contador-Troca, María
Rodríguez, María Isabel
Oliver, Francisco Javier
Fernández-Salguero, Pedro M.
author Contador-Troca, María
author_facet Contador-Troca, María
Rodríguez, María Isabel
Oliver, Francisco Javier
Fernández-Salguero, Pedro M.
author_role author
author2 Rodríguez, María Isabel
Oliver, Francisco Javier
Fernández-Salguero, Pedro M.
author2_role author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Junta de Extremadura
Agencia Extremeña de Cooperación Internacional para el Desarrollo
Ministerio de Sanidad, Servicios Sociales e Igualdad (España)
Red Temática de Investigación Cooperativa en Cáncer (España)
Ministerio de Educación y Ciencia (España)
Instituto de Salud Carlos III
Universidad de Extremadura
European Commission
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Dioxin receptor
Aldehyde dehydrogenase
Tumorigenesis
Lung metastasis
Cancer stem cells
Invasion
topic Dioxin receptor
Aldehyde dehydrogenase
Tumorigenesis
Lung metastasis
Cancer stem cells
Invasion
description [Background] The dioxin (AhR) receptor can have oncogenic or tumor suppressor activities depending on the phenotype of the target cell. We have shown that AhR knockdown promotes melanoma primary tumorigenesis and lung metastasis in the mouse and that human metastatic melanomas had reduced AhR levels with respect to benign nevi.
publishDate 2015
dc.date.none.fl_str_mv 2015
2015
2015
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/122573
url http://hdl.handle.net/10261/122573
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/10.1186/s12943-015-0419-9
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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