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

Int J Cancer. 2005 Sep 10;116(4):500-5. doi: 10.1002/ijc.21119.


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.

Publication types

  • 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.

MeSH terms

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


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