Lack of guanylyl cyclase C, the receptor for Escherichia coli heat-stable enterotoxin, results in reduced polyp formation and increased apoptosis in the multiple intestinal neoplasia (Min) mouse model.
Guanylyl cyclase C (GC-C), a transmembrane receptor for bacterial heat-stable enterotoxin and the mammalian peptides guanylin and uroguanylin, mediates intestinal ion secretion and affects intestinal cell growth via cyclic GMP signaling. In intestinal tumors, GC-C expression is maintained while guanylin and uroguanylin expression is lost, suggesting a role for GC-C activation in tumor formation or growth. We show by in situ hybridization that GC-C expression is retained in adenomas from multiple intestinal neoplasia (Apc(Min/+)) mice. In order to determine the in vivo role of GC-C in intestinal tumorigenesis, we generated Apc(Min/+) mice homozygous for a targeted deletion of the gene encoding GC-C and hypothesized that these mice would have increased tumor multiplicity and size compared to wild-type Apc(Min/+) mice on the same genetic background. In contrast, the absence of GC-C resulted in a reduction of median polyp number by 55%. There was no change in the median diameter of polyps, suggesting no effect on tumor growth. Somatic loss of the wild-type Apc allele, an initiating event in intestinal tumorigenesis, also occurred in polyps from GC-C-deficient Apc(Min/+) mice. We have found increased levels of apoptosis as well as increased caspase-3 and caspase-7 gene expression in the intestines of GC-C-deficient Apc(Min/+) mice compared with Apc(Min/+) mice. We propose that these alterations are a possible compensatory mechanism by which loss of GC-C signaling also affects tumorigenesis.
Mann
Elizabeth A
EA
Division of Digestive Diseases, VA Medical Center and University of Cincinnati, Cincinnati, OH 45267, USA. mannea@uc.edu
Steinbrecher
Kris A
KA
Stroup
Carmen
C
Witte
David P
DP
Cohen
Mitchell B
MB
Giannella
Ralph A
RA
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases / Q000096:biosynthesis; D002471:Cell Transformation, Neoplastic; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006162:Guanylate Cyclase / Q000235:genetics* / Q000502:physiology*; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000503:physiopathology* / Q000662:veterinary; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016609:Neoplasms, Second Primary / Q000235:genetics* / Q000503:physiopathology* / Q000662:veterinary; D011127:Polyps / Q000235:genetics* / Q000503:physiopathology* / Q000662:veterinary; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled; D018000:Receptors, Peptide / Q000235:genetics* / Q000502:physiology*; D015398:Signal Transduction
D018000:Receptors, Peptide; C505409:Casp3 protein, mouse; C505524:Casp7 protein, mouse; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases; D006162:Guanylate Cyclase; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled