Abnormalities of the cadherin-catenin complex in chemically-induced colo-rectal carcinogenesis

Proc Nutr Soc. 2003 Feb;62(1):229-36. doi: 10.1079/pns2003217.

Abstract

Beta-Catenin is a multifunctional protein originally identified as a component of the cadherin cell-cell adhesion complex. It also binds the adenomatous polyposis coli (APC) tumour suppressor which controls beta-catenin cellular levels through its degradation. (beta-Catenin and/or APC mutations result in increased cytoplasmic Beta-catenin and nuclear translocation. The aim of the present study was to examine the expression and cellular localisation of alpha and beta-catenin, p120 and E-cadherin in a chemically-induced mouse model of colo-rectal cancer using 1,2-dimethylhydrazine (DMH). Female Balb/C mice were injected subcutaneously with a solution providing 25 mg DMH base/kg body weight for 17 weeks. Animals were killed and tumours identified in the intestine with a dissecting microscope. Formalin-fixed paraffin-embedded sections of normal and dysplastic colonic mucosa were stained by an indirect avidin-biotin immunohistochemical technique using mouse monoclonal antibodies, and membranous, cytoplasmic and nuclear cellular localisation was assessed by light microscopy. Staining distribution scored as follows: 3, > 90 % positive epithelial cells; 2, >50 % positive epithelial cells; 1, <50 % positive epithelial cells. Non-dysplastic colonic epithelial cells revealed beta-catenin expression at the membrane (33/41 scored 3),areas of cytoplasmic expression (24/41 scored 1) and no nuclear staining. Dysplastic colonic epithelium revealed increased membranous and cytoplasmic, beta-catenin immunoreactivity (39/41 and 38/41 both scored 3) with focal nuclear staining (14/41). Expression patterns for ac-catenin, p120, and E-cadherin were similar to beta-catenin with increased membranous and cytoplasmic immunoreactivity in dysplastic mucosa, although no nuclear staining was observed. Increased cytoplasmic expression and nuclear localisation of beta-catenin are consistent with a possible mutation in its gene, and this finding was in keeping with the mutational analysis of exon 3 by single-strand conformational polymorphism. Increased immunoreactivity of the other catenins also suggests further disruption in catenin regulation. In summary, alterations in the beta-catenin expression and cellular localisation in the DMH-induced tumours are similar to those seen inhuman sporadic colorectal tumours. The DMH is therefore a useful model for studying the abnormalities of the E-cadherin-catenin pathway in colorectal carcinogenesis.

MeSH terms

  • Animals
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Cell Adhesion Molecules
  • Colorectal Neoplasms / chemically induced
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Disease Models, Animal
  • Female
  • Humans
  • Immunohistochemistry
  • Mice
  • Mice, Inbred BALB C
  • Polymorphism, Single-Stranded Conformational
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Translocation, Genetic
  • beta Catenin

Substances

  • CTNNB1 protein, human
  • CTNNB1 protein, mouse
  • Cadherins
  • Cell Adhesion Molecules
  • Cytoskeletal Proteins
  • Trans-Activators
  • beta Catenin