Background: Vitamin D exerts anti-inflammatory actions both in vitro and in murine models of colitis. In previous studies, we demonstrated that vitamin D protects against the development of colitis by maintaining the integrity of the intestinal mucosal barrier. Objective: We sought to evaluate whether deficient serum 25 hydroxyvitamin D [25(OH)D] concentrations are associated with increased mucosal inflammation, a loss of epithelial junctional proteins, and an increase in mucosal inflammatory cytokines in patients with ulcerative colitis (UC). Design: We prospectively enrolled 230 subjects with UC. Serum 25(OH)D concentrations were compared with the Mayo endoscopic score, the total Mayo score, and histologic activity. Colonic mucosal expression concentrations of vitamin D receptor (VDR), E-cadherin, zonula occluden 1 (ZO-1), occludin, claudin-2, tumor necrosis factor a (TNF-a), and interleukin 8 (IL-8) were compared between dichotomous groups with low or high serum 25(OH)D concentrations. Results: The mean serum 25(OH)D concentration was 21.8 ng/mL. Subjects stratified by concentrations included 12.6% $30 ng/mL, 45.6% $20 to ,30 ng/mL, 37.4% $10 to ,20 ng/mL, and 4.4% ,10 ng/mL. There was an inverse association between serum 25(OH)D concentrations and mucosal inflammation as assessed by the Mayo endoscopy score (P = 0.01), disease activity as indicated by the total Mayo score (P = 0.001), and histologic activity (P = 0.02). A serum 25(OH)D concentration ,20 ng/mL was associated with decreased mucosal transcript and protein expression concentrations of VDR, E-cadherin, and occludin as well as decreased protein expression of ZO-1, whereas TNF-a and IL-8 mucosal transcript expression concentrations were increased. Conclusions: In UC patients, serum 25(OH)D concentration is inversely correlated with mucosal inflammation and disease activity. These results, coupled with the findings that serum 25(OH)D concentrations correlate with the mucosal expression of VDR as well as epithelial junction proteins and inversely with proinflammatory cytokines, suggest that vitamin D deficiency may contribute to UC inflammation by disrupting epithelial barrier function.Am J Clin Nutr 2016;104:113-20.
Purpose Epidermal growth factor receptors (EGFR) are required for tumor promotion by Western diet (WD). The metalloprotease, ADAM17 activates EGFR by releasing pro-EGFR ligands. ADAM17 is regulated by G-protein coupled receptors, including CXCR4. Here we investigated CXCR4-ADAM17 crosstalk and examined the role of ADAM17 in tumorigenesis. Experimental Design We used CXCR4 inhibitor, AMD3100 and ADAM17 inhibitor, BMS566394 to assess CXCR4-ADAM17 crosstalk in colon cancer cells. We compared expression of CXCR4 ligand, CXCL2, and ADAM17 in mice fed WD versus standard diet. Separately, mice were treated with marimastat, a broad-spectrum ADAM17 inhibitor, or AMD3100 to assess EGFR activation by ADAM17 and CXCR4. Using Apc mutant Min mice, we investigated effects of ADAM17/10 inhibitor INCB3619 on tumorigenesis. To assess effects of colonocyte ADAM17, mice with ADAM17 conditional deletion were treated with azoxymethane (AOM). ADAM17 expression was also compared in colonocytes from primary human colon cancers and adjacent mucosa. Results CXCL12 treatment activated colon cancer cell EGFR signals, and CXCR4 or ADAM17 blockade reduced this activation. In vivo, WD increased CXCL12 in stromal cells and TGFα in colonocytes. Marimastat or AMD3100 caused >50% reduction in EGFR signals (p<0.05). In Min mice, INCB3619 reduced EGFR signals in adenomas and inhibited intestinal tumor multiplicity (p<0.05). In the AOM model, colonocyte ADAM17 deletion reduced EGFR signals and colonic tumor development (p<0.05). Finally, ADAM17 was up-regulated >2.5-fold in human malignant colonocytes. Conclusions ADAM17 is a WD-inducible enzyme activated by CXCL12-CXCR4 signaling, suggesting the pathway: Western diet->CXCL12->CXCR4->ADAM17->TGFα‐>EGFR. ADAM17 might serve as a druggable target in chemoprevention strategies.
Purpose We previously showed that epidermal growth factor receptor (EGFR) promotes tumorigenesis in the azoxymethane/dextran sulfate sodium (AOM/DSS) model, whereas vitamin D (VD) suppresses tumorigenesis. EGFR-vitamin D receptor (VDR) interactions, however, are incompletely understood. VD inhibits the renin-angiotensin system (RAS), whereas RAS can activate EGFR. We aimed to elucidate EGFR-VDR cross-talk in colorectal carcinogenesis. Experimental Design To examine VDR-RAS interactions, we treated Vdr+/+ and Vdr/− mice with AOM/DSS. Effects of VDR on RAS and EGFR were examined by Westerns, immunostaining and real time PCR. We also examined the effect of vitamin D3 on colonic RAS in Vdr+/+ mice. EGFR regulation of VDR was examined in hypomorphic EgfrWaved2 (Wa2) and Egfrwildtype mice. Ang II-induced EGFR activation was studied in cell culture. Results Vdr deletion significantly increased tumorigenesis, activated EGFR and βcatenin signaling and increased colonic RAS components: including renin and angiotensin II. Dietary VD3 supplementation suppressed colonic renin. Renin was increased in human colon cancers. In studies in vitro, Ang II activated EGFR and stimulated colon cancer cell proliferation by an EGFR-mediated mechanism. Ang II also activated macrophages and colonic fibroblasts. Compared to tumors from EgfrWaved2 mice, tumors from Egfrwildtype mice showed up-regulated Snail1, a suppressor of VDR, and down-regulated VDR. Conclusions VDR suppresses the colonic RAS cascade, limits EGFR signals and inhibits colitis-associated tumorigenesis, whereas EGFR increases Snail1 and down-regulates VDR in colonic tumors. Taken together, these results uncover a RAS-dependent mechanism mediating EGFR and VDR cross-talk in colon cancer.
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