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Global transcriptional response to carbonic anhydrase IX deficiency in the mouse stomach

ABSTRACT: Background Carbonic anhydrases (CAs) are a family of enzymes that regulate pH homeostasis in various tissues. CA IX is an exceptional member of this family because in addition to the basic CA function, it has been implicated in several other physiological and pathological processes. Functions suggested for CA IX include roles in cell adhesion and malignant cell invasion. In addition, CA IX likely regulates cell proliferation and differentiation, which was demonstrated in Car9‾/‾ mice. These mice had gastric pit cell hyperplasia and depletion of chief cells; however, the specific molecular mechanisms behind the observed phenotypes remain unknown. Therefore, we wanted to study the effect of CA IX deficiency on whole-genome gene expression in gastric mucosa. This was done using Illumina Sentrix Mouse-6 Expression BeadChip arrays. The expression of several genes with notable fold-change values was confirmed by QRT-PCR. Results CA IX deficiency caused the induction of 86 genes and repression of 46 genes in the gastric mucosa. There was 92.9% concordance between the results obtained by microarray analysis and QRT-PCR. The differentially expressed genes included those involved in developmental processes and cell differentiation. In addition, CA IX deficiency altered the expression of genes responsible for immune responses and downregulated the expression of several digestive enzymes. Conclusions Microarray analysis identified several potential genes whose altered expression could explain the disturbed cell lineage phenotype in the Car9‾/‾ gastric mucosa. The results also indicated a novel role for CA IX in the regulation of immunologic processes and digestion. These findings reinforce the concept that the main role of CA IX is not the regulation of pH in the stomach mucosa. Instead, it is needed for proper function of several physiological processes.

ORGANISM(S): Mus musculus

PROVIDER: GSE20981 | GEO | 2010/07/01

SECONDARY ACCESSION(S): PRJNA124487

REPOSITORIES: GEO

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Project description:Background: Intestinal metaplasia (IM) is a gastric precancerous lesion that precedes the development of gastric cancer in up to 3.77 cases/1000 person-years. It consists in a trans-differentiation process of gastric to intestinal tissue. Two histological subtypes exist, complete (CIM) and incomplete (IIM), the latter having higher progression rates to gastric cancer . Our objective was to identify molecular processes responsible for the tumoral transition from intestinal metaplasia to GC and the initial steps of this lesion Methods: We used expression microarray to compare the transcriptome of intestinal metaplasia subtypes that progress to gastric cancer (IIM-GC and CIM-GC) after a follow-up period with respect to those that do not progress (IIM control and CIM control). Also, IM-NoGC (IM control, comprising both IIM and CIM Control) was compared with healthy gastric mucosa. Differentially expressed genes were obtained and functional analyses (GSEA and IPA softwares) were performed. Some deregulated genes were validated by qPCR. Results: Histological subtypes of intestinal metaplasia that progress or not to GC differ less among them than to healthy mucosa. Incomplete intestinal metaplasia has a higher number of over-expressed carcinogenic genes and molecular processes than the complete subtype. Most relevant molecular processes and genes in this group include antigenic processing, inflammation, activation of cell cycle and cell proliferation, oncogenes and tumor suppressors. When IM-NoGC is compared with healthy gastric mucosa new identified transcripts include TRIM, TMEM, homeobox, transporters and nucleolar RNAs SNORDs116. We confirm previously reported processes such us intestinal differentiation, metabolism of lipids and of xenobiotics and identify new ones such as non tumoral Warburg effect and melatonin degradation. Conclusions: Differentially expressed genes and molecular processes have been identified for the first time in intestinal metaplasia that progress to gastric cancer. New genes and molecular processes have also been identified in intestinal metaplasia in comparison with healthy gastric mucosa.

Project description:Background: The molecular basis of segment specific epithelial functions of the stomach and bowel has not been established. Regionally unique molecular properties of epithelial cells can be identified using cell-specific gene expression in each epithelial region by comparative mRNA analysis. Aim: To describe segment-specific epithelial mRNA content by comparative mRNA analysis of purified epithelial cell suspensions of stomach, small and large bowel. Results: 12% of all annotated genes show segment specific enrichment. The gastric (>3000 genes) and ileal (519 genes) mucosa show the most diverse expression profile. (a) Stomach: The gastric mucosa expresses the machinery for acid secretion, digestive enzyme release, and hormone release by gastric enteroendocrine cells. Associated with acid secretion is a specific set of K+, Cl-, and bicarbonate channels. Novel is a pathway for glucose and fatty acid sensing, iodine and glutamate uptake, and taurine synthesis. Specific sets of transcription factors control epithelial (Barx1, Runx) and enteroendocrine (FoxA2/N4) cell differentiation. (b) Small Bowel: This epithelium expresses genes coding for a unique fructose/glucose uptake and utilization mechanism. Enteroendocrine signalling to the gastric function is present. The upper portion expresses genes for iron uptake, bicarbonate secretion, and detoxification of food contents. Epithelial differentiation is transcriptionally controlled by Meis2/Pdx1 and Onecut 2. Expression of digestive enzymes, lipid/bile acid uptake and utilization increases distally. The ileal epithelium is also involved in innate and acquired immune defence, regulation of motility, and electrolyte and water re-absorption. Transcriptional regulation of enterocyte and goblet cell differentiation is mainly controlled by increasing expression of Cdx1 and 2. (c) Colon: This epithelium is mainly involved in Ca++-, K+, and water re-absorption, fatty acid uptake and sensing, and innate and acquired immune defence. Epithelial differentiation is controlled by Hox transcription factors in addition to Cdx1/2. Conclusion: This regional survey of gene expression by the GI tract epithelium reveals unique epithelial properties, raising several important questions as to the role of the proteins encoded in gut physiology.

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Global transcriptional response to carbonic anhydrase IX deficiency in the mouse stomach

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