1α,25-dihydroxycholecalciferol increases the expression of vascular endothelial growth factor in C3H10T1/2 mouse embryo fibroblasts
1α,25-dihydroxycholecalciferol increases the expression of vascular endothelial growth factor in C3H10T1/2 mouse embryo fibroblasts
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DOI：
10.1093/jn/134.9.2244
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发表时间：
2004-09-01
影响因子：
4.2
通讯作者：
Teegarden, D
中科院分区：
文献类型：
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作者：
Levine, MJ;Teegarden, D
有证据表明，生物活性维生素D，1，25-二羟基胆钙化醇[1，25（OH）（2）D-3]，可以抑制致癌作用。由于血管生成是至关重要的致癌作用，1，25（OH）（2）D-3的调节促血管生成血管内皮生长因子（VEGF）的分泌进行了研究，在细胞模型的多阶段致癌作用。来自1，25（OH）（2）D-3处理的C3 H10 T（1）/（2）小鼠成纤维细胞及其Harvey ras癌基因转染的对应物（rasneo 11 a细胞）的条件培养基诱导人脐静脉内皮细胞（HUVEC）增殖（分别为1.3和0.3倍，P < 0.05），表明1，25（OH）（2）D-3改变了细胞的血管生成表型。1，25（OH）（2）D-3诱导C3 H10 T（1）/（2）细胞和rasneo 11 a细胞分泌VEGF，分别是对照组的2倍和3倍（P <0.05），但rasneo 11 a细胞分泌VEGF的比例低于C3 H10 T（1）/（2）细胞（97%，P <0.005）。MCF 10A和MCF 10Aras细胞（一种多阶段癌变的人乳腺上皮细胞模型）经1，25（OH）（2）D-3处理后，对VEGF释放的影响相似。在C3 H10 T（1）/（2）细胞中，1，25（OH）（2）D-3以剂量依赖的方式（5-100 nmol/L）激活VEGF启动子（最大60%），所有剂量均诱导VEGF分泌（P < 0.05）。1，25（OH）（2）D-3在2 ~ 24 h诱导VEGF mRNA表达（接近50%），VEGF释放在8 h显著增加并持续24 h。随着C3 H10 T（1）/（2）细胞生长的更加融合，VEGF mRNA表达和释放下降，而1，25（OH）（2）D-3刺激的VEGF变化幅度在融合培养中（3.3倍RNA; 3.5倍释放）比在亚融合培养中（50%RNA; 100%释放）更大（P < 0.05）。因此，1，25（OH）（2）D-3增加VEGF分泌，在C3 H10 T（1）/（2）细胞中，这可能是通过激活VEGF启动子和诱导基因表达。这些数据有助于理解1，25（OH）（2）D-3在正常和疾病状态下调节血管生成中的作用。
Evidence suggests that biologically active vitamin D, 1,25-dihydroxycholecalciferol [1,25(OH)(2)D-3], may inhibit carcinogenesis. Because angiogenesis is crucial to carcinogenesis, 1,25(OH)(2)D-3 regulation of proangiogenic vascular endothelial growth factor (VEGF) secretion was investigated in cellular models for multistage carcinogenesis. Conditioned media from 1,25(OH)(2)D-3,-treated C3H10T(1)/(2) mouse fibroblasts and their Harvey ras-oncogene transfected counterparts (rasneo11a cells) induced human umbilical vein endothelial cell (HUVEC) proliferation (1.3 and 0.3 times, respectively, P < 0.05), suggesting that 1,25(OH)(2)D-3 altered the angiogenic phenotype of the cells. Although rasneo11a cells secreted less VEGF than C3H10T(1)/(2) cells (97%, P < 0.005), 1,25(OH)(2)D-3 induced C3H10T(1)/(2) and rasneo11a cells to secrete 2 and 3 times, respectively, more VEGF than controls (P < 0.05). Similar effects on VEGF release occurred after 1,25(OH)(2)D-3 treatment of MCF10A and MCF10Aras cells, a human breast epithelial cell model for multistage carcinogenesis. In C3H10T(1)/(2) cells, 1,25(OH)(2)D-3 activated the VEGF promoter in a dose-dependent (5-100 nmol/L) manner (maximum 60%) and all doses induced VEGF secretion (P < 0.05). 1,25(OH)(2)D-3 induced VEGF mRNA expression (similar to50%) from 2 through 24 h; VEGF release was significantly increased at 8 h and sustained for 24 h. VEGF mRNA expression and release declined as C3H10T(1)/(2) cells grew more confluent, whereas the magnitude of 1,25(OH)(2)D-3-Stimulated changes in VEGF was greater in confluent (3.3 times RNA; 3.5 times release) than in subconfluent (50% RNA; 100% release) cultures (P < 0.05). Thus, 1,25(OH)(2)D-3 increases VEGF secretion, and in C3H10T(1)/(2) cells, this is likely through activation of the VEGF promoter and induction of gene expression. These data contribute to understanding the role 1,25(OH)(2)D-3 plays in regulation of angiogenesis in normal compared with disease states.