E-cadherin Mediates the Preventive Effect of Vitamin D3 in Colitis-associated Carcinogenesis

Abstract

Vitamin D3 is beneficial in ameliorating or preventing inflammation and carcinogenesis. Here, we evaluated if vitamin D3 has a preventive effect on colitis-associated carcinogenesis. Administration of azoxymethane (AOM), followed with dextran sulfate sodium (DSS), was used to simulate colitis-associated colon cancer in mice. The supplement of vitamin D3 at different dosages (15, 30, 60 IU·g·w), started before AOM or immediately after DSS treatment (post 60), was sustained to the end of the experiment. Dietary vitamin D3 significantly reduced the number of tumors and tumor burden in a dose-dependent manner. Of note, vitamin D3 in high doses showed significant preventive effects on carcinogenesis regardless of administration before or after AOM-DSS treatment. Cell proliferation decreased in vitamin D3 groups compared with the control group after inhibition of expression of β-catenin and its downstream target gene cyclin D1 in the colon. In vitro, vitamin D3 reduced the transcriptional activity and nuclear level of β-catenin, and it also increased E-cadherin expression and its binding affinity for β-catenin. Moreover, repression of E-cadherin was rescued by supplemental vitamin D3 in mouse colons. Taken together, our results indicate that vitamin D3 effectively suppressed colonic carcinogenesis in the AOM-DSS mouse model. Our findings further suggest that upregulation of E-cadherin contributes to the preventive effect of vitamin D3 on β-catenin activity.

Repurposing vitamin D for treatment of human malignancies via targeting tumor microenvironment

“…1,25(OH) 2 D 3 -induced VDR translocation can bind β -catenin to the VDRE of vitamin D target genes, thereby inhibiting the transcriptional activity of WNT downstream targets 144 . It was also found that 1,25(OH) 2 D 3 inhibited WNT/ β -catenin signaling through induction of E-cadherin and the WNT inhibitor DKK1 in colon cancer cells, functioning as a multilevel suppressor of WNT/ β -catenin signaling pathway 145 , 146 , 147 , 148 , 149 . E-cadherin is associated with epithelial phenotype of cancer cells and loss of E-cadherin causes invasiveness of cancer cells.…”

Vitamin D Signaling in Inflammation and Cancer: Molecular Mechanisms and Therapeutic Implications

“…Moreover, it induces the expression of the extracellular inhibitor of Wnt signaling, Dickkopf (DKK)-1. Collectively, 1,25(OH) 2 D 3 functions as a multi-level suppressor of WNT/β- catenin signaling pathway [ 129 , 131 , 132 , 133 , 134 , 135 ].…”

Losartan and Vitamin D Inhibit Colonic Tumor Development in a Conditional Apc-Deleted Mouse Model of Sporadic Colon Cancer

“…Some of these differences may reflect differences in species (rat vs. mouse), different amounts of dietary fat (standard vs. high fat), and different VD doses. Our laboratory showed that global deletion of the Vdr gene increased inflammation-associated colon cancer, and other groups showed that dietary VD could suppress such tumors (6,32,33). Colitis-associated tumors, however, constitute only a small fraction of colon cancers found in humans.…”