Fernandez-Garcia Nuria Isabel, Palmer Hector G, Garcia Marta, Gonzalez-Martin Alicia, del Rio Marcela, Barettino Domingo, Volpert Olga, Muñoz Alberto, Jimenez Benilde
Instituto de Investigaciones Biomedicas CSIC-UAM, Madrid, Spain.
Oncogene. 2005 Sep 29;24(43):6533-44. doi: 10.1038/sj.onc.1208801.
1alpha,25-Dihydroxyvitamin D3 (1alpha,25(OH)2D3) has antitumor activity in addition to its classical action on calcium metabolism and bone tissue biology. It is thought to regulate the expression of multiple target genes and thus modulate processes critical for tumor growth and metastases. Here we show that 1alpha,25(OH)2D3 differentially regulates the expression of Id1 and Id2 genes, members of a family of transcriptional regulators of cell proliferation and differentiation. 1alpha,25(OH)2D3 induced epithelial differentiation in SW480-ADH human colon carcinoma cell line by promoting expression of the proteins implicated in adherent junction formation, including E-cadherin, and by inhibiting beta-catenin transcriptional activity. 1alpha,25(OH)2D3 activated the human Id1 gene promoter and rapidly induced Id1 RNA and protein. Ectopic overexpression of Id1 was not sufficient to induce E-cadherin, which was critical for the morphological changes induced by 1alpha,25(OH)2D3 in SW480-ADH cells. Conversely, Id2 transcription rate, RNA and protein levels were decreased by 1alpha,25(OH)2D3. Id2 downregulation by 1alpha,25(OH)2D3 mediated the antiproliferative effect of 1alpha,25(OH)2D3 on SW480-ADH cells. In addition, we showed that 1alpha,25(OH)2D3 changed the levels of the inducer of angiogenesis, vascular endothelial growth factor and the potent antiangiogenic factor thrombospondin-1, leading to a balanced change in the angiogenic potential of SW480-ADH human colon carcinoma cells.
1α,25 - 二羟基维生素D3（1α,25(OH)2D3）除了对钙代谢和骨组织生物学具有经典作用外，还具有抗肿瘤活性。它被认为可调节多个靶基因的表达，从而调节对肿瘤生长和转移至关重要的过程。在此我们表明，1α,25(OH)2D3对Id1和Id2基因的表达有差异调节作用，这两个基因是细胞增殖和分化转录调节因子家族的成员。1α,25(OH)2D3通过促进与黏附连接形成相关的蛋白质（包括E - 钙黏蛋白）的表达，并抑制β - 连环蛋白的转录活性，诱导SW480 - ADH人结肠癌细胞系发生上皮分化。1α,25(OH)2D3激活人Id1基因启动子并迅速诱导Id1 RNA和蛋白质。Id1的异位过表达不足以诱导E - 钙黏蛋白，而E - 钙黏蛋白对1α,25(OH)2D3在SW480 - ADH细胞中诱导的形态变化至关重要。相反，1α,25(OH)2D3降低了Id2的转录速率、RNA和蛋白质水平。1α,25(OH)2D3介导的Id2下调介导了1α,25(OH)2D3对SW480 - ADH细胞的抗增殖作用。此外，我们表明1α,25(OH)2D3改变了血管生成诱导因子血管内皮生长因子和强效抗血管生成因子血小板反应蛋白 - 1的水平，导致SW480 - ADH人结肠癌细胞血管生成潜力的平衡变化。
