Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina.
Mol Carcinog. 2014 Feb;53 Suppl 1(0 1):E130-9. doi: 10.1002/mc.22054. Epub 2013 Aug 31.
Recently, a reciprocal relationship between calcitriol and epithelial-to-mesenchymal transition has been described. Therefore, we hypothesized that calcitriol (1α,25-dihydroxyvitamin D₃) would enhance radiation sensitivity in colorectal cancer regulated by epithelial mesenchymal transition. Vitamin-D receptor, E-cadherin and vimentin protein as well as E-cadherin, Snail and Slug mRNA levels were assessed in a panel of human colorectal cancer cell lines at baseline and in response calcitriol. We defined cell lines as calcitriol sensitive based on demonstrating an enhanced epithelial phenotype with increased E-cadherin, reduced vimentin and decreased expression of Snail and Slug as well as decreased cellular migration in response to calcitriol. In calcitriol sensitive cells, including DLD-1 and HCT116, 24 h calcitriol pre-treatment enhanced the radiation sensitivity by 2.3- and 2.6-fold, respectively, at 4 Gy (P < 0.05). In contrast, SW620 cells with high baseline mesenchymal features including high Slug and vimentin expression with low E-cadherin expression demonstrated no significant radiation sensitizing response to calcitriol treatment. Similarly, transfection of Slug in the calcitriol sensitive colon cancer cell lines, DLD-1 and HCT 116, completely inhibited the radiation sensitizing effect of calcitriol. Collectively, we demonstrate that calcitriol can enhance the therapeutic effects of radiation in colon cancer cells and Slug expression mitigates this observed effect potentially representing an effective biomarker for calcitriol therapy.
最近，已经描述了钙三醇和上皮-间充质转化之间的相互关系。因此，我们假设钙三醇（1α,25-二羟维生素 D₃）将增强结直肠癌细胞中由上皮间质转化调节的辐射敏感性。在一组人结直肠癌细胞系中，评估了维生素-D 受体、E-钙粘蛋白和波形蛋白蛋白以及 E-钙粘蛋白、Snail 和 Slug mRNA 水平，基线和钙三醇反应。我们根据在钙三醇反应中表现出增强的上皮表型、增加的 E-钙粘蛋白、减少的波形蛋白和减少的 Snail 和 Slug 表达以及减少的细胞迁移来定义钙三醇敏感的细胞系。在钙三醇敏感的细胞系中，包括 DLD-1 和 HCT116，24 h 钙三醇预处理分别增强了 4 Gy 时的辐射敏感性 2.3 倍和 2.6 倍（P < 0.05）。相比之下，基线间充质特征较高的 SW620 细胞，包括高 Slug 和波形蛋白表达，E-钙粘蛋白表达较低，对钙三醇治疗没有明显的辐射增敏反应。同样，Slug 在钙三醇敏感的结肠癌细胞系 DLD-1 和 HCT116 中的转染完全抑制了钙三醇的辐射增敏作用。总的来说，我们证明钙三醇可以增强结肠癌细胞的放射治疗效果，Slug 表达减轻了这种观察到的效果，可能代表钙三醇治疗的有效生物标志物。
