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

✍ Scribed by Elizabeth A. Mann; Kris A. Steinbrecher; Carmen Stroup; David P. Witte; Mitchell B. Cohen; Ralph A. Giannella

• Publisher: John Wiley and Sons
• Year: 2005
• Tongue: French
• Weight: 363 KB
• Volume: 116
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.21119

✦ Synopsis

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. Published 2005 Wiley‐Liss, Inc.