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Pro-Inflammatory Cytokines Trigger the Overexpression of Tumour-Related Splice Variant RAC1B in Polarized Colorectal Cells

2022-03-09Journal article Open access
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dc.contributor.authorPereira, Joana F. S.
dc.contributor.authorBessa, Cláudia
dc.contributor.authorMatos, Paulo
dc.contributor.authorJordan, Peter
dc.date.accessioned2023-01-12T11:25:51Z
dc.date.available2023-01-12T11:25:51Z
dc.date.issued2022-03-09
dc.description.abstractSimple Summary: Tumours are now known to develop more quickly when the tumour cell mass is located in a tissue that shows signs of chronic inflammation. Under such conditions, inflammatory cells from the surrounding tumour microenvironment provide survival signals to which cancer cells respond. We have previously found that some colorectal tumours overexpress the protein RAC1B that sustains tumour cell survival. Here we used a colon mucosa-like in vitro cell model and found that the presence of cancer-associated fibroblasts and pro-inflammatory macrophages stimulated colorectal cells to increase their RAC1B levels. Under these conditions, the secreted survival signals were analysed, and interleukin-6 identified as the main trigger for the increase in RAC1B levels. The results contribute to understand the tumour-promoting effect of inflammation at the molecular level.pt_PT
dc.description.abstractAbstract: An inflammatory microenvironment is a tumour-promoting condition that provides survival signals to which cancer cells respond with gene expression changes. One example is the alternative splicing variant Rat Sarcoma Viral Oncogene Homolog (Ras)-Related C3 Botulinum Toxin Substrate 1 (RAC1)B, which we previously identified in a subset of V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF)-mutated colorectal tumours. RAC1B was also increased in samples from inflammatory bowel disease patients or in an acute colitis mouse model. Here, we used an epithelial-like layer of polarized Caco-2 or T84 colorectal cancer (CRC) cells in co-culture with fibroblasts, monocytes or macrophages and analysed the effect on RAC1B expression in the CRC cells by RT-PCR, Western blot and confocal fluorescence microscopy. We found that the presence of cancer-associated fibroblasts and M1 macrophages induced the most significant increase in RAC1B levels in the polarized CRC cells, accompanied by a progressive loss of epithelial organization. Under these conditions, we identified interleukin (IL)-6 as the main trigger for the increase in RAC1B levels, associated with Signal Transducer and Activator of Transcription (STAT)3 activation. IL-6 neutralization by a specific antibody abrogated both RAC1B overexpression and STAT3 phosphorylation in polarized CRC cells. Our data identify that pro-inflammatory extracellular signals from stromal cells can trigger the overexpression of tumour-related RAC1B in polarized CRC cells. The results will help to understand the tumour-promoting effect of inflammation and identify novel therapeutic strategies.pt_PT
dc.description.sponsorshipWork in the authors’ laboratory was supported by Fundação para a Ciência e Tecnologia (FCT) (through grant UID/MULTI/04046/2019 to Research Unit BioISI, grant PTDC/BIA-MOL/28386/2017, and fellowship BD/109162/2015 to J.F.S.P.) and by the Portuguese association of the intestinal inflammatory disease (grant GEDII 2013 to P.J.).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationCancers (Basel) . 2022 Mar 9;14(6):1393. doi: 10.3390/cancers14061393pt_PT
dc.identifier.doi10.3390/cancers14061393pt_PT
dc.identifier.issn2072-6694
dc.identifier.urihttp://hdl.handle.net/10400.18/8432
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherMDPIpt_PT
dc.relationMicroenvironmental effects on alternative splicing in malignant progression of colorectal tumor cells
dc.relationBiosystems & Integrative Sciences Institute
dc.relationEffect of an inflammatory microenvironment on alternative splicing-mediated gene expression plasticity in colorectal cells
dc.relation.publisherversionhttps://www.mdpi.com/2072-6694/14/6/1393pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectColorectal Cancerpt_PT
dc.subjectRAC1Bpt_PT
dc.subjectRAC1pt_PT
dc.subjectInterleukinpt_PT
dc.subjectMacrophagept_PT
dc.subjectInflammationpt_PT
dc.subjectSignal Transductionpt_PT
dc.subjectVias de Transdução de Sinal e Patologias Associadaspt_PT
dc.titlePro-Inflammatory Cytokines Trigger the Overexpression of Tumour-Related Splice Variant RAC1B in Polarized Colorectal Cellspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleMicroenvironmental effects on alternative splicing in malignant progression of colorectal tumor cells
oaire.awardTitleBiosystems & Integrative Sciences Institute
oaire.awardTitleEffect of an inflammatory microenvironment on alternative splicing-mediated gene expression plasticity in colorectal cells
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FBIA-MOL%2F28386%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FMulti%2F04046%2F2019/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F109162%2F2015/PT
oaire.citation.issue6pt_PT
oaire.citation.startPage1393pt_PT
oaire.citation.titleCancerspt_PT
oaire.citation.volume14pt_PT
oaire.fundingStream3599-PPCDT
oaire.fundingStream6817 - DCRRNI ID
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.embargofctAcesso de acordo com política editorial da revista.pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublication04d4989e-a18e-4287-bc19-a3d9ee1c7430
relation.isProjectOfPublication35168786-8dfc-4a00-9759-dab3669fe1ae
relation.isProjectOfPublicationa70bea5c-3110-4af1-8e2a-dc548ed7b0e3
relation.isProjectOfPublication.latestForDiscovery04d4989e-a18e-4287-bc19-a3d9ee1c7430

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