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A pro-inflammatory microenvironment triggers overexpression of tumor-related RAC1B in polarized colorectal cancer cells

2021-10-05Conference object Restricted access
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dc.contributor.authorJoana, Pereira
dc.contributor.authorCláudia, Bessa
dc.contributor.authorVânia, Gonçalves
dc.contributor.authorMatos, Paulo
dc.contributor.authorJordan, Peter
dc.date.accessioned2022-03-03T18:41:00Z
dc.date.available2022-07-01T00:30:21Z
dc.date.issued2021-10-05
dc.description.abstractAn inflammatory microenvironment is a tumor-promoting condition that provides survival signals to which cancer cells respond with changes in their gene expression. One key regulatory mechanism is alternative splicing. For example, RAC1B is a RAC1 alternative splicing variant that we previously identified in a subset of BRAF-mutated colorectal tumors and that was found increased in colon mucosa under inflammatory conditions, such as samples from inflammatory bowel disease patients or following experimentally-induced acute colitis in a mouse model. Based on these findings, the main goal of this work was to determine which pro-inflammatory signals from stromal cells lead to an increase in RAC1B expression levels in colorectal cancer (CRC) cells. For this, we used a physiologically relevant epithelium-like monolayer of fully polarized Caco-2 CRC cells grown on porous membrane inserts, and then co-cultured underneath with stromal cells, including fibroblasts, monocytes and macrophages. RAC1B expression was analyzed in Caco-2 cells by RT-qPCR, Western blot and confocal fluorescence microscopy. Co-culture experiments revealed that the combined presence of cancer-associated fibroblasts and/or M1 macrophages induced an increase in RAC1B levels in Caco-2 cells, accompanied by a loss of epithelial organization. Moreover, using a human inflammation antibody array, we were able to identify from the conditioned co-culture media that cytokine IL-6 was associated with increased RAC1B expression. Remarkably, the incubation of polarized Caco-2 cells with purified IL-6 was sufficient per se to trigger an increase in RAC1B expression in a dose-dependent manner, and the presence of anti-IL-6 antibodies during the co-culture prevented the increase. Overall, our data indicate that pro-inflammatory signals from the microenvironment can modulate RAC1B expression in colon epithelial cells. Since RAC1B was shown to sustain tumor cell survival and promote escape form oncogene-induced senescence, the data further strengthen the causal connection between inflammatory conditions and the development of colorectal cancer.pt_PT
dc.description.sponsorshipFCTpt_PT
dc.description.versionN/Apt_PT
dc.identifier.urihttp://hdl.handle.net/10400.18/7976
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.subjectColorectal Cancerpt_PT
dc.subjectTumor Microenvironmentpt_PT
dc.subjectRAC1Bpt_PT
dc.subjectInflammationpt_PT
dc.subjectSplicingpt_PT
dc.subjectVias de Transdução de Sinal e Patologias Associadaspt_PT
dc.titleA pro-inflammatory microenvironment triggers overexpression of tumor-related RAC1B in polarized colorectal cancer cellspt_PT
dc.typeconference object
dspace.entity.typePublication
oaire.citation.conferencePlace(online)pt_PT
oaire.citation.titleEACR conference Goodbye Flat Biology: Next Generation Cancer Models, 5-6 October 2021pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typeconferenceObjectpt_PT

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