A role for the vitamin D pathway in non-intestinal lesions in genetic and carcinogen models of colorectal cancer and in familial adenomatous polyposis
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Yong-Sik Bong1,*, Shahin Assefnia1,*, Therese Tuohy2, Deborah W Neklason2, Randall W Burt2, Jaeil Ahn3, Paul J Bueno De Mesquita1, Stephen W. Byers1
1Georgetown-Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University School of Medicine, Washington, DC, United States of America
2Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States of America
3Department of Biostatistics, Bioinformatics and Biomathematics, Georgetown University School of Medicine, Washington, DC, United States of America
*These authors contributed equally to this work
Stephen W, email: [email protected]
Keywords: gardner’s syndrome, anal cancer, vitamin D receptor, azoxymethane, colon cancer
Received: April 13, 2016 Accepted: October 11, 2016 Published: October 19, 2016
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.
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