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.

Abstract

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.

• Authors: Elizabeth A Mann, Kris A Steinbrecher, Carmen Stroup, David P Witte, Mitchell B Cohen, Ralph A Giannella
• Journal: International journal of cancer (Int J Cancer) Vol. 116 Issue 4 Pg. 500-5 (Sep 10 2005) ISSN: 0020-7136 [Print] United States
• PMID: 15825168 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
• Copyright: Published 2005 Wiley-Liss, Inc.

Chemical References

• Receptors, Peptide
• Casp3 protein, mouse
• Casp7 protein, mouse
• Caspase 3
• Caspase 7
• Caspases
• Guanylate Cyclase
• Receptors, Enterotoxin
• Receptors, Guanylate Cyclase-Coupled

Topics

• Animals
• Apoptosis
• Caspase 3
• Caspase 7
• Caspases (biosynthesis)
• Cell Transformation, Neoplastic
• Disease Models, Animal
• Gene Expression Regulation
• Guanylate Cyclase (genetics, physiology)
• Intestinal Neoplasms (genetics, physiopathology, veterinary)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neoplasms, Second Primary (genetics, physiopathology, veterinary)
• Polyps (genetics, physiopathology, veterinary)
• Receptors, Enterotoxin
• Receptors, Guanylate Cyclase-Coupled
• Receptors, Peptide (genetics, physiology)
• Signal Transduction