Vitamin D receptor activity and prevention of colonic hyperproliferation and oxidative stress.
Unimpaired vitamin D action has been implicated in human cancer prevention. We have previously demonstrated the effectiveness of 1 alpha-dihydroxyvitamin D3 (1,25-D3) to reduce proliferation and increase differentiation in human colon cancer cells. The aim of this study was to investigate, on the one hand, expression of the vitamin D receptor (VDR) and of 25-hydroxyvitamin D(3)-1 alpha-hydroxylase (1 alpha-hydroxylase) in human normal and malignant colonic tissue and, on the other hand, to determine consequences of reduced or lacking VDR action in a VDR knockout mouse model. In low-grade malignancies of the human colon we found increased VDR and 1 alpha-hydroxylase mRNA expression. However, in late-stage high-grade tumors the vitamin D system is severely compromised. In the mouse colon we found an inverse relationship between VDR levels and proliferation in colon descendens, a tissue known to be specifically affected by nutrients during carcinogenesis. Expression of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, was significantly augmented with complete loss of VDR. These data suggest that genomic 1,25-D(3) action is necessary to protect against nutrition-linked hyperproliferation and oxidative DNA damage.
Kállay
E
E
Department of Pathophysiology, University of Vienna Medical School, Waehringer Guertel 18-20, Vienna, Austria.
Bareis
P
P
Bajna
E
E
Kriwanek
S
S
Bonner
E
E
Toyokuni
S
S
Cross
H S
HS
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism*; D000080242:8-Hydroxy-2'-Deoxyguanosine; D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects; D003106:Colon / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D004249:DNA Damage / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects*; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018167:Receptors, Calcitriol; D000080242:8-Hydroxy-2'-Deoxyguanosine; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D003849:Deoxyguanosine