The goal of this application is to address RFA-CA-12-015 PQA1: What is the molecular mechanism by which a drug that is chronically used for other indications protects against cancer incidence and mortality? Vitamin D (VD) is a widely and chronically used supplement for maintenance of bone health and for treatment of osteoporosis, but a growing body of evidence has indicated that VD has potent chemopreventive effects against colon cancer by unknown mechanisms. Thus the central question to be addressed is: What is the molecular mechanism by which Vitamin D prevents colon cancer? Colon cancer is a leading cause of cancer- related deaths in the US. Low VD status is associated with increased colon cancer incidence, chemopreventive effects of VD have been demonstrated in colon cancer models, and large randomized clinical trials are being conducted to evaluate VD's chemopreventive efficacy against colon cancer in humans, but the mechanism underlying VD's anti-colon cancer activity remains to be defined. Secondary bile acids (BA) are potent colon cancer promoters. VD is known to affect colonic secondary BA levels by regulating host and colonic bacterial BA metabolism. Therefore we hypothesize that VD regulation of secondary BA levels is a key molecular mechanism underlying VD's chemopreventive activity against colon cancer. Moreover, the tumor-promoting secondary BA lithocholic acid (LCA) can also activate the vitamin D receptor (VDR), and LCA-VDR signals, like VD-VDR signals, also promote secondary BA catabolism by inducing Cyp3A, which can paradoxically limit LCA's tumor-promoting effects. Therefore we also hypothesize that VDR signals activated by VD or LCA limit secondary BA levels, thus mitigating tumor promotion by BAs. We will test these hypotheses using colon cancer models in genetically engineered mice with altered vitamin D hormone or VDR levels, and in gnotobiotic mice with altered bacterial secondary BA production.
In Aim 1 we will determine the VDR-dependent host and microbe mechanisms that regulate Western diet-induced secondary BAs and colonic tumorigenesis. We will assess secondary BA levels and colonic tumorigenesis in WT, VDR(-/-) and transgenic mice over-expressing epithelial VDR that are fed Western diet or VD supplemented diet.
In Aim 2 we will dissect the role of VD- independent LCA-VDR signals in colonic tumorigenesis. We will compare effects of Western diet or dietary LCA on secondary BAs and colonic tumorigenesis in WT, VDR(-/-), Cyp27b1(-/-) and VDR(-/-)/Cyp27b1(-/-) mice. Cyp27b1(-/-) and VDR(-/-)/Cyp27b1(-/-) mice cannot synthesize VD hormone, allowing us to dissect the chemopreventive effects of LCA-VDR signals without confounding effects of endogenous VD hormone.
In Aim 3 we will assess the role of microbial 7?-dehydroxylase (7-DH) in VD chemoprevention. We will compare tumorigenesis in gnotobiotic mice mono-associated with Lactobacillus acidophilus lacking 7-DH to mice also associated with Clostridium scindens expressing 7-DH fed Western diet or diet supplemented with VD. These studies will greatly advance our understanding of chemopreventive mechanisms of VD against colon cancer.
Colon cancer is a leading cause of cancer-related deaths in the US. Western diets increase the risk of colon cancer in part by increasing colonic bile acids. Vitamin D is a widely and chronically used supplement for maintenance of bone health and for treatment of osteoporosis. A growing body of evidence has indicated that vitamin D has potent chemopreventive effects against colon cancer by unknown mechanisms. Since vitamin D controls several key steps in bile acid metabolism, the goal of this proposal is to use genetically engineered mice to address whether vitamin D suppresses colon cancer by altering bile acid metabolism.
|He, Lei; Liu, Tianjing; Shi, Yongyan et al. (2018) Gut Epithelial Vitamin D Receptor Regulates Microbiota-Dependent Mucosal Inflammation by Suppressing Intestinal Epithelial Cell Apoptosis. Endocrinology 159:967-979|
|Mustafi, Reba; Dougherty, Urszula; Mustafi, Devkumar et al. (2017) ADAM17 is a Tumor Promoter and Therapeutic Target in Western Diet-associated Colon Cancer. Clin Cancer Res 23:549-561|
|Du, Jie; Wei, Xinzhi; Ge, Xin et al. (2017) Microbiota-Dependent Induction of Colonic Cyp27b1 Is Associated With Colonic Inflammation: Implications of Locally Produced 1,25-Dihydroxyvitamin D3 in Inflammatory Regulation in the Colon. Endocrinology 158:4064-4075|
|Shi, Yongyan; Liu, Tianjing; He, Lei et al. (2016) Activation of the Renin-Angiotensin System Promotes Colitis Development. Sci Rep 6:27552|
|Meckel, Katherine; Li, Yan Chun; Lim, John et al. (2016) Serum 25-hydroxyvitamin D concentration is inversely associated with mucosal inflammation in patients with ulcerative colitis. Am J Clin Nutr 104:113-20|
|Du, Jie; Chen, Yunzi; Shi, Yongyan et al. (2015) 1,25-Dihydroxyvitamin D Protects Intestinal Epithelial Barrier by Regulating the Myosin Light Chain Kinase Signaling Pathway. Inflamm Bowel Dis 21:2495-506|
|Golan, Maya Aharoni; Liu, Weicheng; Shi, Yongyan et al. (2015) Transgenic Expression of Vitamin D Receptor in Gut Epithelial Cells Ameliorates Spontaneous Colitis Caused by Interleukin-10 Deficiency. Dig Dis Sci 60:1941-7|
|Wang, Jiaolong; Chen, Li; Chen, Bohao et al. (2015) Chronic Activation of the Renin-Angiotensin System Induces Lung Fibrosis. Sci Rep 5:15561|
|Li, Yan Chun; Chen, Yunzi; Du, Jie (2015) Critical roles of intestinal epithelial vitamin D receptor signaling in controlling gut mucosal inflammation. J Steroid Biochem Mol Biol 148:179-83|
|Chen, Peili; Li, Yan Chun; Toback, F Gary (2015) AMP-18 Targets p21 to Maintain Epithelial Homeostasis. PLoS One 10:e0125490|
Showing the most recent 10 out of 12 publications