Associations between Vitamin D-Binding Protein Isotypes, Circulating 25(OH)D Levels, and Vitamin D Metabolite Uptake in Colon Cancer Cells
Associations between Vitamin D-Binding Protein Isotypes, Circulating 25(OH)D Levels, and Vitamin D Metabolite Uptake in Colon Cancer Cells
复制标题
DOI：
10.1158/1940-6207.capr-13-0269
复制
发表时间：
2014-04-01
影响因子：
3.3
通讯作者：
Jurutka, Peter W.
中科院分区：
文献类型：
--
作者：
Hibler, Elizabeth A.;Jacobs, Elizabeth T.;Jurutka, Peter W.
维生素D代谢物作为癌症化学预防剂已被广泛研究。基于rs7041和rs 4588双倍型的GC-球蛋白（GC）同种型对1 α，25-二羟基维生素D（1，25（OH）（2）D）和25-羟基维生素D（25（OH）D）具有不同的亲和力，这可能影响循环代谢物浓度以及细胞水平的递送。我们在403名熊去氧胆酸（UDCA）临床试验参与者中评估了GC同种型和循环维生素D代谢产物浓度之间的相关性。在用乙醇载体、1，25（OH）（2）D或25（OH）D处理的人结肠癌（HCT-116）细胞中以及用已知GC同种型个体的血浆处理的人结肠癌（HCT-116）细胞中评价代谢物摄取。使用基于哺乳动物-2-杂交和维生素D响应元件的荧光素酶测定来测量维生素D受体途径活化作为代谢物摄取的标志物。回归分析显示，1F_2、1S_2和2_2亚型的血清25（OH）D浓度显著低于1S_1S亚型（P < 0.01）。与这些体内观察结果一致，细胞数据显示，GC同种型仅在较高浓度下25（OH）D摄取变化较小（P = 0.05），而GC同种型在不同浓度和测定方法下1，25（OH）（2）D摄取差异显著（P < 0.01）。1F_1S和1F_2同种型在1，25（OH）（2）D处理下产生最大的报告基因诱导，而25（OH）D处理下激活变化较小，2_2同种型在较低浓度下表现出增加的诱导。这些结果表明，维生素D代谢物浓度和向结肠细胞的递送可能不仅因GC同种型而异，而且某些同种型可能比25（OH）D更有效地递送1，25（OH）（2）D。总的来说，这些结果可能有助于识别癌症风险人群和靶向化学预防的潜在接受者。(c)2014年AACR。
Vitamin D metabolites have been extensively studied as cancer chemopreventive agents. Gc-globulin (GC) isotypes, based on rs7041 and rs4588 diplotypes, have varying affinities for 1 alpha, 25-dihydroxyvitamin D (1,25(OH)(2)D) and 25-hydroxyvitamin D (25(OH)D), which may affect circulating metabolite concentration as well as delivery at the cellular level. We evaluated associations between GC isotype and circulating vitamin D metabolite concentrations in 403 ursodeoxycholic acid ( UDCA) clinical trial participants. Metabolite uptake was evaluated in human colon cancer (HCT-116) cells treated with ethanol vehicle, 1,25(OH)(2)D, or 25(OH)D, and with plasma from individuals with known GC isotype. Mammalian-2-hybrid and vitamin D-responsive element-based luciferase assays were used to measure the vitamin D receptor pathway activation as a marker for metabolite uptake. Regression analysis demonstrated significantly lower serum 25(OH) D concentration for clinical trial participants with 1F_2, 1S_2, or 2_2 isotypes (P < 0.01) compared with 1S_1S. Consistent with these in vivo observations, cellular data revealed that 25 ( OH) D uptake varied less by GC isotype only at the higher concentration tested (P = 0.05), while 1,25 (OH)(2)D uptake differed markedly by GC isotype across concentration and assay ( P < 0.01). The 1F_1S and 1F_2 isotypes produced the greatest reporter gene induction with 1,25(OH)(2)D treatment and, while activation varied less with 25(OH)D, the 2_2 isotype demonstrated increased induction at the lower concentration. These results suggest that vitamin D metabolite concentration and delivery to colon cells may vary not only by GC isotype, but also that certain isotypes may more effectively deliver 1,25(OH)(2)D versus 25(OH)D. Overall, these results may help identify populations at risk for cancer and potential recipients of targeted chemoprevention.(c) 2014 AACR.