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WNT6 is a novel oncogenic prognostic biomarker in human glioblastoma

2018-09-09Journal article Open access
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dc.contributor.authorGonçalves, C.
dc.contributor.authorVieira de Castro, J.
dc.contributor.authorPojo, M.
dc.contributor.authorMartins, E.
dc.contributor.authorQueirós, S.
dc.contributor.authorChautard, E.
dc.contributor.authorTaipa, Ricardo
dc.contributor.authorPires, M.
dc.contributor.authorPinto, A.
dc.contributor.authorPardal, F.
dc.contributor.authorCustódia, C.
dc.contributor.authorFaria, C.
dc.contributor.authorClara, C.
dc.contributor.authorReis, R.
dc.contributor.authorSousa, N.
dc.contributor.authorCosta, B.
dc.date.accessioned2020-03-24T11:06:28Z
dc.date.available2020-03-24T11:06:28Z
dc.date.issued2018-09-09
dc.description.abstractGlioblastoma (GBM) is a universally fatal brain cancer, for which novel therapies targeting specific underlying oncogenic events are urgently needed. While the WNT pathway has been shown to be frequently activated in GBM, constituting a potential therapeutic target, the relevance of WNT6, an activator of this pathway, remains unknown. Methods: WNT6 protein and mRNA levels were evaluated in GBM. WNT6 levels were silenced or overexpressed in GBM cells to assess functional effects in vitro and in vivo. Phospho-kinase arrays and TCF/LEF reporter assays were used to identify WNT6-signaling pathways, and significant associations with stem cell features and cancer-related pathways were validated in patients. Survival analyses were performed with Cox regression and Log-rank tests. Meta-analyses were used to calculate the estimated pooled effect. Results: We show that WNT6 is significantly overexpressed in GBMs, as compared to lower-grade gliomas and normal brain, at mRNA and protein levels. Functionally, WNT6 increases typical oncogenic activities in GBM cells, including viability, proliferation, glioma stem cell capacity, invasion, migration, and resistance to temozolomide chemotherapy. Concordantly, in in vivo orthotopic GBM mice models, using both overexpressing and silencing models, WNT6 expression was associated with shorter overall survival, and increased features of tumor aggressiveness. Mechanistically, WNT6 contributes to activate typical oncogenic pathways, including Src and STAT, which intertwined with the WNT pathway may be critical effectors of WNT6-associated aggressiveness in GBM. Clinically, we establish WNT6 as an independent prognostic biomarker of shorter survival in GBM patients from several independent cohorts. Conclusion: Our findings establish WNT6 as a novel oncogene in GBM, opening opportunities to develop more rational therapies to treat this highly aggressive tumor.pt_PT
dc.description.sponsorshipThe authors extend their acknowledgments to the families who contributed to this study. Financial support was provided by grants from the FCT - Foundation for Science and Technology (PTDC/SAU-GMG/113795/2009 and IF/00601/2012 to B.M.C.; SFRH/BD/92786/2013 to C.S.G.; SFRH/BD/88121/2012 to J.V.C.; SFRH/BD/81042/2011 to M.P.; SFRH/BD/93443/2013 to S.Q.) and Fundação Calouste Gulbenkian (B.M.C.), by FEDER funds through the Operational Programme Competitiveness Factors - COMPETE and National Funds through FCT under the project POCI-01-0145-FEDER-007038; by the project NORTE-01-0145-FEDER-000013 and NORTE-01-0246-FEDER-000012, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF); and by the project NORTE-01-0145-FEDER-000023, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationGonçalves CS, Vieira de Castro J, Pojo M, et al. WNT6 is a novel oncogenic prognostic biomarker in human glioblastoma. Theranostics. 2018;8(17):4805–4823. Published 2018 Sep 9. doi:10.7150/thno.25025pt_PT
dc.identifier.doi10.7150/thno.25025pt_PT
dc.identifier.issn1838-7640
dc.identifier.urihttp://hdl.handle.net/10400.16/2341
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherIvyspring International Publisherpt_PT
dc.relation.publisherversionhttps://www.thno.org/v08p4805.htmpt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/pt_PT
dc.subjectbiomarkerpt_PT
dc.subjectglioblastomapt_PT
dc.subjectoncogenept_PT
dc.subjectprognosispt_PT
dc.subjectWNT6pt_PT
dc.subjectWNT pathwaypt_PT
dc.titleWNT6 is a novel oncogenic prognostic biomarker in human glioblastomapt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876-PPCDTI/PTDC%2FSAU-GMG%2F113795%2F2009/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBD%2F88121%2F2012/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBD%2F81042%2F2011/PT
oaire.citation.conferencePlaceAustraliapt_PT
oaire.citation.endPage4823pt_PT
oaire.citation.issue17pt_PT
oaire.citation.startPage4805-4823pt_PT
oaire.citation.titleTheranosticspt_PT
oaire.citation.volume8pt_PT
oaire.fundingStream5876-PPCDTI
oaire.fundingStreamSFRH
oaire.fundingStreamSFRH
person.familyNameFerreira Taipa
person.givenNameRicardo Jorge
person.identifier.ciencia-idE316-D53D-8537
person.identifier.orcid0000-0002-9260-0227
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
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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relation.isAuthorOfPublication.latestForDiscovery97a7bf34-226a-4dc2-ae31-d0f86030cb52
relation.isProjectOfPublication10cff1f0-b40b-4bbe-af5c-c7ca94e993cb
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