| Autor: |
Haibo Xu, Posner, Gary H., Stevenson, Michael, Campbell, Frederick C. |
| Předmět: |
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| Zdroj: |
Carcinogenesis; Aug2010, Vol. 31 Issue 8, p1434-1441, 8p, 1 Chart, 5 Graphs |
| Abstrakt: |
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. [ABSTRACT FROM PUBLISHER] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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