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Aberrant MEK5/ERK5 signalling contributes to human colon cancer progression via NF-κB activation

2015Journal article Open access
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dc.contributor.authorSimões, André
dc.contributor.authorPereira, D. M.
dc.contributor.authorGomes, S. E.
dc.contributor.authorBrito, H.
dc.contributor.authorCarvalho, Tânia
dc.contributor.authorFrench, A.
dc.contributor.authorCastro, Rui E.
dc.contributor.authorSteer, C. J.
dc.contributor.authorThibodeau, S. N.
dc.contributor.authorRodrigues, Cecília M. P.
dc.contributor.authorBorralho, P. M.
dc.date.accessioned2022-05-25T15:28:04Z
dc.date.available2022-05-25T15:28:04Z
dc.date.issued2015
dc.description© 2015 Macmillan Publishers Limited All rights reserved. Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0pt_PT
dc.description.abstractThis study was designed to evaluate MEK5 and ERK5 expression in colon cancer progression and to ascertain the relevance of MEK5/ERK5 signalling in colon cancer. Expression of MEK5 and ERK5 was evaluated in 323 human colon cancer samples. To evaluate the role of MEK5/ERK5 signalling in colon cancer, we developed a stable cell line model with differential MEK5/ERK5 activation. Impact of differential MEK5/ERK5 signalling was evaluated on cell cycle progression by flow cytometry and cell migration was evaluated by wound healing and transwell migration assays. Finally, we used an orthotopic xenograft mouse model of colon cancer to assess tumour growth and progression. Our results demonstrated that MEK5 and ERK5 are overexpressed in human adenomas (P<0.01) and adenocarcinomas (P<0.05), where increased ERK5 expression correlated with the acquisition of more invasive and metastatic potential (P<0.05). Interestingly, we observed a significant correlation between ERK5 expression and NF-κB activation in human adenocarcinomas (P<0.001). We also showed that ERK5 overactivation significantly accelerated cell cycle progression (P<0.05) and increased cell migration (P<0.01). Furthermore, cells with overactivated ERK5 displayed increased NF-κB nuclear translocation and transcriptional activity (P<0.05), together with increased expression of the mesenchymal marker vimentin (P<0.05). We further demonstrated that increased NF-κB activation was associated with increased IκB phosphorylation and degradation (P<0.05). Finally, in the mouse model, lymph node metastasis was exclusively seen in orthotopically implanted tumours with overactivated MEK5/ERK5, and not in tumours with inhibited MEK5/ERK5. Our results suggested that MEK5/ERK5/NF-κB signalling pathway is important for tumour onset, progression and metastasis, possibly representing a novel relevant therapeutic target in colon cancer treatment.pt_PT
dc.description.sponsorshipThis study was supported by Fundação para a Ciência e Tecnologia (HMSP-ICT/0018/2011, SFRH/BD/96517/2013, SFRH/BD/88619/2012 and SFRH/BD/79356/2011).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationCell Death Dis. 2015 Apr 9;6(4):e1718pt_PT
dc.identifier.doi10.1038/cddis.2015.83pt_PT
dc.identifier.eissn2041-4889
dc.identifier.urihttp://hdl.handle.net/10451/53175
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringer Naturept_PT
dc.relationTREAT LIVER DISEASES BY TARGETING HEPATOCYTE NECROPTOSIS
dc.relationTACKLING COLON CANCER STEM CELLS WITH MICRORNAS
dc.relationMIR-143, -145 AND -21 MODULATION IN COLON CANCER - FROM ANTICANCER ACTIVITY TO DRUG SENSITIZATION
dc.relationEXPLORING MEK5/ERK5 SIGNALING AND MIRNAS AS THERAPEUTIC STRATEGIES IN COLON CANCER
dc.relation.publisherversionhttps://www.nature.com/cddis/pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.titleAberrant MEK5/ERK5 signalling contributes to human colon cancer progression via NF-κB activationpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleTREAT LIVER DISEASES BY TARGETING HEPATOCYTE NECROPTOSIS
oaire.awardTitleTACKLING COLON CANCER STEM CELLS WITH MICRORNAS
oaire.awardTitleMIR-143, -145 AND -21 MODULATION IN COLON CANCER - FROM ANTICANCER ACTIVITY TO DRUG SENSITIZATION
oaire.awardTitleEXPLORING MEK5/ERK5 SIGNALING AND MIRNAS AS THERAPEUTIC STRATEGIES IN COLON CANCER
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/HMSP-ICT%2F0018%2F2011/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBD%2F96517%2F2013/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBD%2F88619%2F2012/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBD%2F79356%2F2011/PT
oaire.citation.issue4pt_PT
oaire.citation.titleCell Death & Diseasept_PT
oaire.citation.volume6pt_PT
oaire.fundingStream3599-PPCDT
oaire.fundingStreamOE
oaire.fundingStreamOE
oaire.fundingStreamOE
person.familyNameSimões
person.familyNameCarvalho
person.familyNameCastro
person.familyNameRodrigues
person.givenNameAndré
person.givenNameTânia
person.givenNameRui
person.givenNameCecilia
person.identifier30919
person.identifier.ciencia-id4C10-5743-02F8
person.identifier.ciencia-id3C1C-A6C2-71ED
person.identifier.ciencia-idDC18-39A7-F287
person.identifier.orcid0000-0002-0489-6356
person.identifier.orcid0000-0002-5283-5013
person.identifier.orcid0000-0002-7417-0091
person.identifier.orcid0000-0002-4829-754X
person.identifier.ridE-6393-2015
person.identifier.ridJ-3656-2013
person.identifier.ridI-2975-2013
person.identifier.ridM-3572-2013
person.identifier.scopus-author-id25653983600
person.identifier.scopus-author-id7202085681
person.identifier.scopus-author-id7202508239
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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