Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Arturo Duperier 4, 28029 Madrid, Spain.
J Steroid Biochem Mol Biol. 2010 Jul;121(1-2):106-9. doi: 10.1016/j.jsbmb.2010.01.014. Epub 2010 Feb 6.
Vitamin D receptor (VDR) mediates the antitumoral action of the active vitamin D metabolite 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3). However, VDR expression is lost during colon cancer progression, possibly causing unresponsiveness to 1,25(OH)2D3. Although several mechanisms responsible for resistance to 1,25(OH)2D3 action in different types of cancer had been reported, none explained the loss of VDR expression. We have found that the transcription factors Snail1 and Snail2, known as inducers of epithelial-to-mesenchymal transition (EMT), inhibit VDR expression and block 1,25(OH)2D3 action in colon cancer cells. Snail1 and Snail2 have an additive repressing effect on VDR gene promoter. These effects are specific to the Snail family, as other transcription factors that function as EMT inducers do not inhibit VDR expression in colon cancer cells. Moreover, we also found that the RNA expression of SNAI1 and SNAI2 is upregulated in human colorectal tumors and inversely correlates with that of VDR. Our results suggest that high levels of SNAIL1 and SNAIL2 are a probable cause of VDR downregulation and 1,25(OH)2D3 unresponsiveness in colon cancer. In addition, they may contribute to the improvement of protocols for the clinical use of vitamin D compounds, as they indicate that advanced colon cancer patients overexpressing SNAIL1 and SNAIL2 are not suitable candidates for this therapy.
维生素 D 受体(VDR)介导活性维生素 D 代谢物 1α,25-二羟维生素 D3(1,25(OH)2D3)的抗肿瘤作用。然而,VDR 的表达在结肠癌进展过程中丢失,可能导致对 1,25(OH)2D3 无反应。尽管已经报道了几种导致不同类型癌症对 1,25(OH)2D3 作用产生抗性的机制,但没有一种机制能够解释 VDR 表达的丧失。我们发现,转录因子 Snail1 和 Snail2,作为上皮-间充质转化(EMT)的诱导物,抑制结肠癌细胞中的 VDR 表达并阻断 1,25(OH)2D3 作用。Snail1 和 Snail2 对 VDR 基因启动子具有加性抑制作用。这些作用是 Snail 家族特有的,因为作为 EMT 诱导物发挥作用的其他转录因子不会抑制结肠癌细胞中的 VDR 表达。此外,我们还发现 SNAI1 和 SNAI2 的 RNA 表达在人结直肠肿瘤中上调,并与 VDR 的表达呈负相关。我们的结果表明,SNAIL1 和 SNAIL2 的高水平可能是 VDR 下调和结肠癌中 1,25(OH)2D3 无反应的一个可能原因。此外,它们可能有助于改善维生素 D 化合物临床应用的方案,因为它们表明过度表达 SNAIL1 和 SNAIL2 的晚期结肠癌患者不适合这种治疗。