Abstract
Vitamin D is implicated in the etiology of cancers of the gastrointestinal tract, usually characterized by alteration in the APC/β-catenin/TCF tumor suppressor pathway. The vitamin D receptor (VDR) is also implicated in cardiovascular and skin diseases as well as in immunity. Activated VDR can indirectly alter β-catenin nuclear localization and directly suppress β-catenin/TCF mediated transcriptional activity. We treated VDR null mice with the carcinogen azoxymethane (AOM) and generated mice bearing a mutated APC (hypomorph) on a VDR null background (Apc1638N/+Vdr−/−). VDR null mice do not develop GI or extra-colonic tumors but loss of VDR decreased intestinal tumor latency and increased progression to adenocarcinoma in both models. AOM treatment of VDR null mice also caused squamous cell carcinoma of the anus. Although levels and distribution of total or activated β-catenin in the epithelial component of tumors were unaffected by loss of VDR, β-catenin dependent cyclin D1 expression was affected suggesting a direct VDR effect on β-catenin co-activator activity. Extra-colonic mucosa manifestations in Apc1638N/+Vdr−/− animals included increased nuclear β-catenin in submucosal stromal cells, spleno- and cardiomegaly and large epidermoid cysts characteristic of the FAP variant, Gardner's syndrome. Consistent with this, SNPs in the VDR, vitamin D binding protein and CYP24 as well as mutations in APC distal to codon 850 were strongly associated with Gardners syndrome in a cohort of 457 FAP patients, This work suggests that alterations in the vitamin D/VDR axis are important in Gardner's syndrome, as well as in the etiology of anal cancer.
Highlights
Familial adenomatous polyposis (FAP) is an inherited colorectal cancer syndrome that is classically characterized by the early onset of hundreds to thousands of adenomas in the rectum and colon [1]
Consistent with this, SNPs in the vitamin D receptor (VDR), vitamin D binding protein and CYP24 as well as mutations in adenomatous polyposis coli (APC) distal to codon 850 were strongly associated with Gardners syndrome in a cohort of 457 FAP patients, This work suggests that alterations in the vitamin D/VDR axis are important in Gardner’s syndrome, as well as in the etiology of anal cancer
The most active form of vitamin D (1, 25-dihydroxyvitamin D3) inhibits cell proliferation, induces differentiation of human colon cancer cells by regulation of E-cadherin expression and by sequestrating the formation of transcriptionally active β-catenin/TCF complex through the direct binding of VDR to β-catenin [16,17,18,19,20]. Taken together these studies indicate that variation of vitamin D itself or vitamin D pathway genes may affect colorectal cancer development initiated by activated β-catenin signaling, but may associate with the occurrence of extracolonic manifestations in FAP patients
Summary
Familial adenomatous polyposis (FAP) is an inherited colorectal cancer syndrome that is classically characterized by the early onset of hundreds to thousands of adenomas in the rectum and colon [1]. The most active form of vitamin D (1, 25-dihydroxyvitamin D3) inhibits cell proliferation, induces differentiation of human colon cancer cells by regulation of E-cadherin expression and by sequestrating the formation of transcriptionally active β-catenin/TCF complex through the direct binding of VDR to β-catenin [16,17,18,19,20]. Taken together these studies indicate that variation of vitamin D itself or vitamin D pathway genes may affect colorectal cancer development initiated by activated β-catenin signaling, but may associate with the occurrence of extracolonic manifestations in FAP patients. We go on to demonstrate an association between extracolonic lesions, polymorphisms of vitamin D pathway genes and site of APC mutation in a cohort of 457 FAP patients
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