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Chronic inflammation and carcinogenesis caused by intestinal specific ablation of integrin alpha6 beta4

ABSTRACT: Inflammatory bowel diseases (IBD) in humans are characterized by chronic inflammation and gastrointestinal tissue damage, caused by a combination of genetic and environmental factors. It has been largely documented that IBD frequently lead to colorectal cancers (CRC). The identification of causative factors of IBD is thus essential to understand CRC progression and develop therapeutical approaches. Models have been described in which molecular alterations are combined with inflammatory treatments in order to recapitulate IBD-associated CRC. Here, we describe a mouse line, α6fl/fl Villin-Cre, in which inactivation of the gene encoding the integrin alpha-6 subunit (ITGA6) specifically in the intestinal mucosa results into chronic inflammation and intestinal carcinogenesis. In these mice, the loss of integrin alpha-6 beta-4, a receptor mediating the attachment of epithelial cells to laminins, leads to epithelial detachment, hyperplasia, chronic inflammation, rectal prolapses, and ultimately adenocarcinomas. Alterations of differentiation affecting mucus secreting (goblet) cells as well as changes in expression of essential intestinal transcription factors were detected. Thus alpha-6 beta-4 integrin is a key factor for the maintenance of intestinal integrity and its loss may represent a risk factor for tumor progression associated with IBD.

ORGANISM(S): Mus musculus

PROVIDER: GSE37749 | GEO | 2016/07/07

SECONDARY ACCESSION(S): PRJNA163077

REPOSITORIES: GEO

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Project description:Inflammatory bowel diseases (IBD) in humans are characterized by chronic inflammation and gastrointestinal tissue damage, caused by a combination of genetic and environmental factors. It has been largely documented that IBD frequently lead to colorectal cancers (CRC). The identification of causative factors of IBD is thus essential to understand CRC progression and develop therapeutical approaches. Models have been described in which molecular alterations are combined with inflammatory treatments in order to recapitulate IBD-associated CRC. Here, we describe a mouse line, Î±6fl/fl Villin-Cre, in which inactivation of the gene encoding the integrin alpha-6 subunit (ITGA6) specifically in the intestinal mucosa results into chronic inflammation and intestinal carcinogenesis. In these mice, the loss of integrin alpha-6 beta-4, a receptor mediating the attachment of epithelial cells to laminins, leads to epithelial detachment, hyperplasia, chronic inflammation, rectal prolapses, and ultimately adenocarcinomas. Alterations of differentiation affecting mucus secreting (goblet) cells as well as changes in expression of essential intestinal transcription factors were detected. Thus alpha-6 beta-4 integrin is a key factor for the maintenance of intestinal integrity and its loss may represent a risk factor for tumor progression associated with IBD. Transcriptome analysis of RNA from normal versus inflamed and carcinomatous rectal mucosa of Î±6 integrin deficient intestinal epithelium mice was performed. RNAs were prepared from 5 adenocarcinomas, which were macrodissected from the rectal prolapses and 4 flanking inflamed rectal mucosa of 53-80 week-old Î±6fl/fl Villin-Cre mice. RNAs from normal rectal mucosa were obtained by rectum scraping from 4 matched control animals. The transcriptome analysis was performed using the Affymetrix Mouse Gene 1.0 ST arrays. Images were processed using affymetrix GeneChipÂ® Command ConsoleÂ® Software (AGCC) (version 2.0) and numerical value were generated using Affymetrix Expression Consoleâ¢ Software (version 1.1).

Project description:To investigate the detailed molecular mechanisms for the regulatory role of HIF-2α in experimental colitis, microarray gene expression analysis was performed on colon RNA isolated from 6- to 8-week-old Hif-2αF/F, Hif-2αlΔIE mice treated with 3%DSS for 3 days. Background & Aims: Hypoxic inflammation is characterized by decreased oxygen tension in inflammatory foci, and is a notable feature in inflammatory bowel disease (IBD). Hypoxic response is mediated by transcription factors hypoxia-inducible factor (HIF)-1α and HIF-2α, both of which are highly induced in IBD. HIF-1α is a protective factor that limits intestinal barrier dysfunction during inflammation. However, the role of HIF-2α has not been assessed in hypoxic inflammation and IBD. Methods: A hypoxia reporter mouse model was used to test the presence of hypoxia and HIF-2α in dextran sulfate sodium (DSS) and Citrobacter rodentium (C.rod)-induced colitis. The role of HIF-2α in these mouse models of colitis was further assessed in mice with an intestinal epithelium-specific gain- and loss-of-function of HIF-2α. Results: Induction of hypoxia and HIF-2α was confirmed in both murine experimental colitis models and human IBD samples. Disruption of HIF-2α attenuated colonic inflammation whereas stabilization of HIF-2α potentiated inflammation in mouse models of colitis. Interestingly, intestine specific overexpression of HIF-2α but not HIF-1α leads to spontaneous colitis and premature death in mice. Further mechanistic analysis showed that HIF-2α is a driver for pro-inflammatory response and is critical regulator of intestinal epithelial-derived tumor necrosis factor (TNF)-α. Blocking TNF-α completely ameliorated HIF-2α potentiated intestinal inflammation. Conclusions: These data demonstrate that HIF-2α is a critical transcription factor essential in intestinal epithelium elicited inflammatory response. Global gene expression profiling in colon RNAs isolated from 7-week-old Hif-2αF/F (n=6, Shah 007) and Hif-2αΔIE (n=5, Shah 008).

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Chronic inflammation and carcinogenesis caused by intestinal specific ablation of integrin alpha6 beta4

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