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TNFα-mediated activation of NF-κB downregulates sodium-iodide symporter expression in thyroid cells

2020Journal article Open access
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dc.contributor.authorFaria, Márcia
dc.contributor.authorDomingues, Rita
dc.contributor.authorPaixão, Francisca
dc.contributor.authorBugalho, Maria João
dc.contributor.authorMatos, Paulo
dc.contributor.authorSilva, Ana Luísa
dc.date.accessioned2020-02-14T15:15:13Z
dc.date.available2020-02-14T15:15:13Z
dc.date.issued2020
dc.description© 2020 Faria et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.pt_PT
dc.description.abstractThe sodium-iodide symporter (NIS) mediates transport of iodide across the basolateral membrane of thyroid cells. NIS expression in thyroid cancer (TC) cells allows the use of radioactive iodine (RAI) as a diagnostic and therapeutic tool, being RAI therapy the systemic treatment of choice for metastatic disease. Still, a significant proportion of patients with advanced TC lose the ability to respond to RAI therapy and no effective alternative therapies are available. Defective NIS expression is the main reason for impaired iodide uptake in TC and NIS downregulation has been associated with several pathways linked to malignant transformation. NF-κB signaling is one of the pathways associated with TC. Interestingly, NIS expression can be negatively regulated by TNF-α, a bona fide activator of NF-κB with a central role in thyroid autoimmunity. This prompted us to clarify NF-kB’s role in this process. We confirmed that TNF-α leads to downregulation of TSH-induced NIS expression in non-neoplastic thyroid follicular cell-derived models. Notably, a similar effect was observed when NF-κB activation was triggered independently of ligand-receptor specificity, using phorbol-myristate-acetate (PMA). TNF-α and PMA downregulation of NIS expression was reverted when NF-κB-dependent transcription was blocked, demonstrating the requirement for NF-kB activity. Additionally, TNF-α and PMA were shown to have a negative impact on TSH-induced iodide uptake, consistent with the observed transcriptional downregulation of NIS. Our data support the involvement of NF-κB-directed transcription in the modulation of NIS expression, where up- or down-regulation of NIS depends on the combined output to NF-κB of several converging pathways. A better understanding of the mechanisms underlying NIS expression in the context of normal thyroid physiology may guide the development of pharmacological strategies to increase the efficiency of iodide uptake. Such strategies would be extremely useful in improving the response to RAI therapy in refractory-TC.pt_PT
dc.description.sponsorshipThis work was supported by the Fundação para a Ciência e a Tecnologia, grant [PTDC/BIAMOL/31787/2017] from Portugal. MF is recipient of FCT fellowship PD/BD/114388/2016.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationPLoS ONE 15(2): e0228794.pt_PT
dc.identifier.doi10.1371/journal.pone.0228794pt_PT
dc.identifier.eissn1932-6203
dc.identifier.urihttp://hdl.handle.net/10451/41838
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherPLoSpt_PT
dc.relationPTDC/BIAMOL/31787/2017pt_PT
dc.relationTargeting Rac1-signaling to enhance iodide-related cancer therapy
dc.relation.publisherversionhttps://journals.plos.org/plosone/pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.titleTNFα-mediated activation of NF-κB downregulates sodium-iodide symporter expression in thyroid cellspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleTargeting Rac1-signaling to enhance iodide-related cancer therapy
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//PD%2FBD%2F114388%2F2016/PT
oaire.citation.issue2pt_PT
oaire.citation.startPagee0228794pt_PT
oaire.citation.titlePLoS ONEpt_PT
oaire.citation.volume15pt_PT
person.familyNameFaria
person.familyNameCardoso Domingues
person.familyNameBugalho
person.familyNameSilva
person.givenNameMárcia
person.givenNameRita Sofia
person.givenNameMaria João
person.givenNameAna Luísa
person.identifier1596200
person.identifierF-5245-2012
person.identifier.ciencia-id0B12-EF2F-133D
person.identifier.ciencia-idD51C-30D5-71FC
person.identifier.ciencia-id0F14-CA4F-1358
person.identifier.ciencia-idD215-714A-CA06
person.identifier.orcid0000-0002-6601-1138
person.identifier.orcid0000-0001-7130-3795
person.identifier.orcid0000-0003-0357-7350
person.identifier.orcid0000-0002-9379-9696
person.identifier.orcid0000-0002-4839-8279
person.identifier.scopus-author-id35582359500
person.identifier.scopus-author-id7003265109
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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