Abstract 1302: Effect of intestinal-specific Kaiso overexpression on the APC MIN/+ mouse colon cancer model
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AbstractThe canonical Wnt signaling pathway is a crucial regulator of various cellular processes during embryogenesis but when aberrantly activated, it leads to tumorigenesis. The key downstream effector of the Wnt pathway is the Armadillo protein, β-catenin, which was first characterized as a cytoplasmic cofactor for the transmembrane, cell-cell adhesion tumor suppressor, E-cadherin. Recent evidence from our lab and others indicates that another E-cadherin cofactor, p120ctn and its binding partner, the POZ-ZF transcription factor Kaiso, co-regulate a subset of Wnt/β-catenin target genes and antagonize Wnt signaling. Specifically, using a Xenopus model system, we and others found that Kaiso overexpression rescued the β-catenin-induced duplicate axis phenotype; this implicated Kaiso as a negative regulator of Wnt signaling. However, it remains to be determined whether an analogous antagonistic role for Kaiso is conserved in mammals. Indeed, when Kaiso-null mice (which were viable and had no overt developmental defects or tumors) were crossed with the APCMIN/+ mouse model of colon cancer, the progeny had delayed tumor onset and reduced polyp size. This suggested that Kaiso played a positive role in tumor initiation and possibly cell proliferation in mammals. To resolve this discrepancy, we generated intestine-specific Kaiso overexpressing transgenic mice (KaisoTg/+) for subsequent mating with the APCMIN/+ mouse model of colon cancer. Histological analysis of small and large intestines from KaisoTg/+ and non-Tg mice revealed no gross morphological differences. Immunohistochemical (IHC) and immunofluorescence (IF) staining revealed strong nuclear Kaiso staining in intestinal tissues from KaisoTg/+ mice whereas intestinal tissues from non-Tg mice displayed weak cytoplasmic or no Kaiso staining. We detected no difference in β-Catenin expression levels in tissues from KaisoTg/+ mice and their wildtype littermates. This suggests that Kaiso's regulation of WNT signaling is downstream of its main effector β-Catenin. KaisoTg-APCMIN/+ double mutant mice have been generated and surprisingly they display decreased body size and weight, and have a decreased life span when compared to the parentals (i.e. KaisoTg or APCMIN/+). Current studies are aimed at assessing polyp formation and elucidating the expression levels of p120ctn, β-catenin, E-cadherin and cyclinD1 in the KaisoTg-APCMIN/+ intestines.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1302. doi:1538-7445.AM2012-1302
