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Transcriptome profiling of T84 colorectal carcinoma cells treated with receptor guanylyl cyclace C agonist (stable toxin)

ABSTRACT: Receptor guanylyl cyclase C (GC-C) is expressed in the intestinal epithelia and plays a key role in intestinal physiology. Activation of GC-C by its ligands has been shown to regulate proliferation and differentiation of enterocytes along the crypt-villus axis. This study aims to identify genes regulated by GC-C activation and elevation of cGMP in colorectal carcinoma cells. This will help understand the molecular targets and biological pathways regulated by GC-C to bring about cancer cell cytostasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE45531 | GEO | 2014/02/04

SECONDARY ACCESSION(S): PRJNA194541

REPOSITORIES: GEO

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Project description:BACKGROUND Familial diarrheas are mostly severe recessive diseases. Here we describe the clinical picture and dominant genetic cause of a novel disease in 32 members of a Norwegian family. The chronic diarrhea is of early onset, relatively mild, and is combined with increased susceptibility to intestinal inflammation, ileus and oesophagitis. METHODS Whole genome SNP-analysis was used to identify a single candidate locus for dominant diarrhea on chromosome 12, followed by sequencing of the GU2CY gene. This encodes guanylyl cyclase 2C, an intestinal receptor for bacterial heat-stable enterotoxins and the peptides uroguanylin and guanylin. Functional studies of a missense mutation were performed after heterologous expression of the mutant receptor in HEK293T cells. The therapeutic response to metformin, an inhibitor of the cystic fibrosis transmembrane regulator (CFTR), was investigated in 5 patients. RESULTS We identified heterozygosity for the first described pathogenic human mutation (c.2519G>T ) in the GUCY2C gene. The mutant receptor showed increased cGMP production in response to its ligands. This may cause hyperactivation of the CFTR and consequent increased chloride and water secretion from the enterocytes, resulting in chronic diarrhea. Treatment with the CFTR-inhibitor metformin significantly reduced the frequency of stools in affected individuals by 34-45%. CONCLUSIONS Increased GC-C signaling disturbs normal bowel function, as shown by the diverse symptoms in our patients, and seems to have a pro-inflammatory effect, either through increased Cl- secretion or additional effects of elevated cellular cGMP. The importance of genetic variants in the GC-C-CFTR-pathway for conditions like Crohn’s disease and IBS should be further explored. Linkage analysis was performed (Allegro v 2.0) using Affymetrix 250K SNP arrays according to the manufacturer's directions on DNA extracted from peripheral blood samples. This accession number contains the data for 25 individuals of family branch A in the article.

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Transcriptome profiling of T84 colorectal carcinoma cells treated with receptor guanylyl cyclace C agonist (stable toxin)

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