Pro-Inflammatory Cytokines Trigger the Overexpression of Tumour-Related Splice Variant RAC1B in Polarized Colorectal Cells
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.18/8432 |
Resumo: | Simple 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. |
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Pro-Inflammatory Cytokines Trigger the Overexpression of Tumour-Related Splice Variant RAC1B in Polarized Colorectal CellsColorectal CancerRAC1BRAC1InterleukinMacrophageInflammationSignal TransductionVias de Transdução de Sinal e Patologias AssociadasSimple 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.Abstract: 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.Work 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.).MDPIRepositório Científico do Instituto Nacional de SaúdePereira, Joana F. S.Bessa, CláudiaMatos, PauloJordan, Peter2023-01-12T11:25:51Z2022-03-092022-03-09T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.18/8432engCancers (Basel) . 2022 Mar 9;14(6):1393. doi: 10.3390/cancers140613932072-669410.3390/cancers14061393info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-20T15:42:28Zoai:repositorio.insa.pt:10400.18/8432Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:42:55.455122Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Pro-Inflammatory Cytokines Trigger the Overexpression of Tumour-Related Splice Variant RAC1B in Polarized Colorectal Cells |
title |
Pro-Inflammatory Cytokines Trigger the Overexpression of Tumour-Related Splice Variant RAC1B in Polarized Colorectal Cells |
spellingShingle |
Pro-Inflammatory Cytokines Trigger the Overexpression of Tumour-Related Splice Variant RAC1B in Polarized Colorectal Cells Pereira, Joana F. S. Colorectal Cancer RAC1B RAC1 Interleukin Macrophage Inflammation Signal Transduction Vias de Transdução de Sinal e Patologias Associadas |
title_short |
Pro-Inflammatory Cytokines Trigger the Overexpression of Tumour-Related Splice Variant RAC1B in Polarized Colorectal Cells |
title_full |
Pro-Inflammatory Cytokines Trigger the Overexpression of Tumour-Related Splice Variant RAC1B in Polarized Colorectal Cells |
title_fullStr |
Pro-Inflammatory Cytokines Trigger the Overexpression of Tumour-Related Splice Variant RAC1B in Polarized Colorectal Cells |
title_full_unstemmed |
Pro-Inflammatory Cytokines Trigger the Overexpression of Tumour-Related Splice Variant RAC1B in Polarized Colorectal Cells |
title_sort |
Pro-Inflammatory Cytokines Trigger the Overexpression of Tumour-Related Splice Variant RAC1B in Polarized Colorectal Cells |
author |
Pereira, Joana F. S. |
author_facet |
Pereira, Joana F. S. Bessa, Cláudia Matos, Paulo Jordan, Peter |
author_role |
author |
author2 |
Bessa, Cláudia Matos, Paulo Jordan, Peter |
author2_role |
author author author |
dc.contributor.none.fl_str_mv |
Repositório Científico do Instituto Nacional de Saúde |
dc.contributor.author.fl_str_mv |
Pereira, Joana F. S. Bessa, Cláudia Matos, Paulo Jordan, Peter |
dc.subject.por.fl_str_mv |
Colorectal Cancer RAC1B RAC1 Interleukin Macrophage Inflammation Signal Transduction Vias de Transdução de Sinal e Patologias Associadas |
topic |
Colorectal Cancer RAC1B RAC1 Interleukin Macrophage Inflammation Signal Transduction Vias de Transdução de Sinal e Patologias Associadas |
description |
Simple 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. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-03-09 2022-03-09T00:00:00Z 2023-01-12T11:25:51Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.18/8432 |
url |
http://hdl.handle.net/10400.18/8432 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Cancers (Basel) . 2022 Mar 9;14(6):1393. doi: 10.3390/cancers14061393 2072-6694 10.3390/cancers14061393 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
MDPI |
publisher.none.fl_str_mv |
MDPI |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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