Journal Article

Apc<sup>MIN</sup> modulation of vitamin D secosteroid growth control

Haibo Xu, Gary H. Posner, Michael Stevenson and Frederick C. Campbell

in Carcinogenesis

Volume 31, issue 8, pages 1434-1441
Published in print August 2010 | ISSN: 0143-3334
Published online May 2010 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgq098
ApcMIN modulation of vitamin D secosteroid growth control

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  • Clinical Cytogenetics and Molecular Genetics

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A central paradox of vitamin D biology is that 1α,25-(OH)2 D3 exposure inversely relates to colorectal cancer (CRC) risk despite a capacity for activation of both pro- and anti-oncogenic mediators including osteopontin (OPN)/CD44 and E-cadherin, respectively. Most sporadic CRCs arise from adenomatous polyposis coli (APC) gene mutation but understanding of its effects on vitamin D growth control is limited. Here we investigate effects of the ApcMin/+ genotype on 1α,25-(OH)2 D3 regulation of OPN/CD44/E-cadherin signalling and intestinal tumourigenesis, in vivo. In untreated ApcMin/+ versus Apc+/+ intestines, expression levels of OPN and its CD44 receptor were increased, whereas E-cadherin tumour suppressor signalling was attenuated. Treatment by 1α,25-(OH)2 D3 or rationally designed analogues (QW or BTW) enhanced OPN but inhibited expression of CD44, the OPN receptor implicated in cell growth. These treatments also enhanced E-cadherin tumour suppressor activity, characterized by inhibition of β-catenin nuclear localization, T-cell factor 1 and c-myelocytomatosis protein expression in ApcMin/+ intestine. All secosteroids suppressed ApcMin/+-driven tumourigenesis although QW and BTW had lower calcium-related toxicity. Taken together, these data indicate that the ApcMin/+ genotype modulates vitamin D secosteroid actions to promote functional predominance of E-cadherin tumour suppressor activity within antagonistic molecular networks. APC heterozygosity may promote favourable tissue- or tumour-specific conditions for growth control by vitamin D secosteroid treatment.

Journal Article.  6034 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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