The Rac1 splice form Rac1b favors mouse colonic mucosa regeneration and contributes to intestinal cancer progression
Autor(a) principal: | |
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Data de Publicação: | 2018 |
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/10400.18/5799 |
Resumo: | We previously have identified the ectopic expression of Rac1b, an activated and novel splice variant of Rac1, in a subset of human colorectal adenocarcinomas, as well as in inflammatory bowel diseases and in colitis mouse model. Rac1b overexpression has been further evidenced in breast, pancreatic, thyroid, ovarian, and lung cancers. In this context, the aim of our study was to investigate the physiopathological implications of Rac1b in intestinal inflammation and carcinogenesis in vivo. The ectopic expression of Rac1b was induced in mouse intestinal epithelial cells after crossing Rosa26-LSL-Rac1b and villin-Cre mice. These animals were let to age or were challenged with dextran sulfate sodium (DSS) to induce experimental colitis, or either received azoxymethane (AOM)/DSS treatment, or were bred with ApcMin/+ or Il10-/- mice to trigger intestinal tumors. Rac1b ectopic expression increased the intestinal epithelial cell proliferation and migration, enhanced the production of reactive oxygen species, and promoted the Paneth cell lineage. Although Rac1b overexpression alone was not sufficient to drive intestinal neoplasia, it enhanced Apc-dependent intestinal tumorigenesis. In the context of Il10 knockout, the Rac1b transgene strengthened colonic inflammation due to induced intestinal mucosa permeability and promoted cecum and proximal colon carcinogenesis. In contrast, Rac1b alleviated carcinogen/acute inflammation-associated colon carcinogenesis (AOM/DSS). This resulted at least partly from the early mucosal repair after resolution of inflammation. Our data highlight the critical role of Rac1b in driving wound-healing after resolution of intestinal inflammation, and in cooperating with Wnt pathway dysregulation and chronic inflammation to promote intestinal carcinogenesis. |
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The Rac1 splice form Rac1b favors mouse colonic mucosa regeneration and contributes to intestinal cancer progressionIntestinal CancerCancerRAC1bMouse ModelVias de Transdução de Sinal e Patologias AssociadasWe previously have identified the ectopic expression of Rac1b, an activated and novel splice variant of Rac1, in a subset of human colorectal adenocarcinomas, as well as in inflammatory bowel diseases and in colitis mouse model. Rac1b overexpression has been further evidenced in breast, pancreatic, thyroid, ovarian, and lung cancers. In this context, the aim of our study was to investigate the physiopathological implications of Rac1b in intestinal inflammation and carcinogenesis in vivo. The ectopic expression of Rac1b was induced in mouse intestinal epithelial cells after crossing Rosa26-LSL-Rac1b and villin-Cre mice. These animals were let to age or were challenged with dextran sulfate sodium (DSS) to induce experimental colitis, or either received azoxymethane (AOM)/DSS treatment, or were bred with ApcMin/+ or Il10-/- mice to trigger intestinal tumors. Rac1b ectopic expression increased the intestinal epithelial cell proliferation and migration, enhanced the production of reactive oxygen species, and promoted the Paneth cell lineage. Although Rac1b overexpression alone was not sufficient to drive intestinal neoplasia, it enhanced Apc-dependent intestinal tumorigenesis. In the context of Il10 knockout, the Rac1b transgene strengthened colonic inflammation due to induced intestinal mucosa permeability and promoted cecum and proximal colon carcinogenesis. In contrast, Rac1b alleviated carcinogen/acute inflammation-associated colon carcinogenesis (AOM/DSS). This resulted at least partly from the early mucosal repair after resolution of inflammation. Our data highlight the critical role of Rac1b in driving wound-healing after resolution of intestinal inflammation, and in cooperating with Wnt pathway dysregulation and chronic inflammation to promote intestinal carcinogenesis.Springer NatureRepositório Científico do Instituto Nacional de SaúdeKotelevets, LarissaWalker, FrancineMamadou, GodefroyLehy, ThérèseJordan, PeterChastre, Eric2019-02-13T17:00:06Z2018-112018-11-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.18/5799engOncogene. 2018 Nov;37(46):6054-6068. doi: 10.1038/s41388-018-0389-7. Epub 2018 Jul 9.0950-923210.1038/s41388-018-0389-7info:eu-repo/semantics/embargoedAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-20T15:41:04Zoai:repositorio.insa.pt:10400.18/5799Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:40:30.085925Repositório 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 |
The Rac1 splice form Rac1b favors mouse colonic mucosa regeneration and contributes to intestinal cancer progression |
title |
The Rac1 splice form Rac1b favors mouse colonic mucosa regeneration and contributes to intestinal cancer progression |
spellingShingle |
The Rac1 splice form Rac1b favors mouse colonic mucosa regeneration and contributes to intestinal cancer progression Kotelevets, Larissa Intestinal Cancer Cancer RAC1b Mouse Model Vias de Transdução de Sinal e Patologias Associadas |
title_short |
The Rac1 splice form Rac1b favors mouse colonic mucosa regeneration and contributes to intestinal cancer progression |
title_full |
The Rac1 splice form Rac1b favors mouse colonic mucosa regeneration and contributes to intestinal cancer progression |
title_fullStr |
The Rac1 splice form Rac1b favors mouse colonic mucosa regeneration and contributes to intestinal cancer progression |
title_full_unstemmed |
The Rac1 splice form Rac1b favors mouse colonic mucosa regeneration and contributes to intestinal cancer progression |
title_sort |
The Rac1 splice form Rac1b favors mouse colonic mucosa regeneration and contributes to intestinal cancer progression |
author |
Kotelevets, Larissa |
author_facet |
Kotelevets, Larissa Walker, Francine Mamadou, Godefroy Lehy, Thérèse Jordan, Peter Chastre, Eric |
author_role |
author |
author2 |
Walker, Francine Mamadou, Godefroy Lehy, Thérèse Jordan, Peter Chastre, Eric |
author2_role |
author author author author author |
dc.contributor.none.fl_str_mv |
Repositório Científico do Instituto Nacional de Saúde |
dc.contributor.author.fl_str_mv |
Kotelevets, Larissa Walker, Francine Mamadou, Godefroy Lehy, Thérèse Jordan, Peter Chastre, Eric |
dc.subject.por.fl_str_mv |
Intestinal Cancer Cancer RAC1b Mouse Model Vias de Transdução de Sinal e Patologias Associadas |
topic |
Intestinal Cancer Cancer RAC1b Mouse Model Vias de Transdução de Sinal e Patologias Associadas |
description |
We previously have identified the ectopic expression of Rac1b, an activated and novel splice variant of Rac1, in a subset of human colorectal adenocarcinomas, as well as in inflammatory bowel diseases and in colitis mouse model. Rac1b overexpression has been further evidenced in breast, pancreatic, thyroid, ovarian, and lung cancers. In this context, the aim of our study was to investigate the physiopathological implications of Rac1b in intestinal inflammation and carcinogenesis in vivo. The ectopic expression of Rac1b was induced in mouse intestinal epithelial cells after crossing Rosa26-LSL-Rac1b and villin-Cre mice. These animals were let to age or were challenged with dextran sulfate sodium (DSS) to induce experimental colitis, or either received azoxymethane (AOM)/DSS treatment, or were bred with ApcMin/+ or Il10-/- mice to trigger intestinal tumors. Rac1b ectopic expression increased the intestinal epithelial cell proliferation and migration, enhanced the production of reactive oxygen species, and promoted the Paneth cell lineage. Although Rac1b overexpression alone was not sufficient to drive intestinal neoplasia, it enhanced Apc-dependent intestinal tumorigenesis. In the context of Il10 knockout, the Rac1b transgene strengthened colonic inflammation due to induced intestinal mucosa permeability and promoted cecum and proximal colon carcinogenesis. In contrast, Rac1b alleviated carcinogen/acute inflammation-associated colon carcinogenesis (AOM/DSS). This resulted at least partly from the early mucosal repair after resolution of inflammation. Our data highlight the critical role of Rac1b in driving wound-healing after resolution of intestinal inflammation, and in cooperating with Wnt pathway dysregulation and chronic inflammation to promote intestinal carcinogenesis. |
publishDate |
2018 |
dc.date.none.fl_str_mv |
2018-11 2018-11-01T00:00:00Z 2019-02-13T17:00:06Z |
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/10400.18/5799 |
url |
http://hdl.handle.net/10400.18/5799 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Oncogene. 2018 Nov;37(46):6054-6068. doi: 10.1038/s41388-018-0389-7. Epub 2018 Jul 9. 0950-9232 10.1038/s41388-018-0389-7 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/embargoedAccess |
eu_rights_str_mv |
embargoedAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Springer Nature |
publisher.none.fl_str_mv |
Springer Nature |
dc.source.none.fl_str_mv |
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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 |
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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) |
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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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