Apc(MIN) modulation of vitamin D secosteroid growth control.
A central paradox of vitamin D biology is that 1alpha,25-(OH)(2) D(3) 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 Apc(Min/+) genotype on 1alpha,25-(OH)(2) D(3) regulation of OPN/CD44/E-cadherin signalling and intestinal tumourigenesis, in vivo. In untreated Apc(Min/+) versus Apc(+/+) intestines, expression levels of OPN and its CD44 receptor were increased, whereas E-cadherin tumour suppressor signalling was attenuated. Treatment by 1alpha,25-(OH)(2) D(3) 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 beta-catenin nuclear localization, T-cell factor 1 and c-myelocytomatosis protein expression in Apc(Min/+) intestine. All secosteroids suppressed Apc(Min/+)-driven tumourigenesis although QW and BTW had lower calcium-related toxicity. Taken together, these data indicate that the Apc(Min/+) 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.
Xu
Haibo
H
Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Northern Ireland, UK.
Posner
Gary H
GH
Stevenson
Michael
M
Campbell
Frederick C
FC
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics* / Q000502:physiology; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000502:physiology; D003106:Colon / Q000473:pathology; D015179:Colorectal Neoplasms / Q000401:mortality / Q000517:prevention & control; D017931:DNA Primers; D005260:Female; D005838:Genotype; D006801:Humans; D007417:Intestinal Polyps / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D053495:Osteopontin / Q000502:physiology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D018167:Receptors, Calcitriol / Q000235:genetics; D012307:Risk Factors; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D015430:Weight Gain / Q000235:genetics
D025601:Adenomatous Polyposis Coli Protein; D015820:Cadherins; D017931:DNA Primers; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D053495:Osteopontin; D014807:Vitamin D