Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, NY 14642, USA.
Mol Cancer Ther. 2012 Dec;11(12):2621-32. doi: 10.1158/1535-7163.MCT-12-0621. Epub 2012 Oct 1.
In patients with advanced bladder cancer, glucocorticoids are frequently given to reduce acute toxicity, particularly hyperemesis, during chemotherapy, as well as to improve cachectic conditions. However, it remains unclear whether glucocorticoids directly affect the development and progression of bladder cancer through the glucocorticoid receptor pathway. Glucocorticoid receptor expression was first investigated in human bladder cancer lines and tissue microarrays. Then, the effects of dexamethasone on glucocorticoid receptor transcription, cell proliferation, apoptosis/cell cycle, and invasion were examined in bladder cancer lines. Finally, mouse xenograft models for bladder cancer were used to assess the efficacy of dexamethasone on tumor progression. All the cell lines and tissues examined were found to express glucocorticoid receptor. Dexamethasone increased glucocorticoid receptor-mediated reporter activity and cell proliferation, and inhibited apoptosis in the presence or absence of cisplatin. In contrast, dexamethasone suppressed cell invasion, the expression of its related genes [MMP-2/MMP-9, interleukin (IL)-6, VEGF], and the activity of MMP-2/MMP-9, and also induced mesenchymal-to-epithelial transition. In addition, dexamethasone increased IκBα protein levels and cytosolic accumulation of NF-κB. In xenograft-bearing mice, dexamethasone slightly augmented the growth of the inoculated tumors but completely prevented the development of bloody ascites, suggestive of peritoneal dissemination of tumor cells, and actual metastasis. In all these assays, dexamethasone effects were abolished by a glucocorticoid receptor antagonist or glucocorticoid receptor knockdown via RNA interference. Thus, glucocorticoid receptor activation resulted in promotion of cell proliferation via inhibiting apoptosis yet repression of cell invasion and metastasis. These results may provide a basis of developing improved chemotherapy regimens, including or excluding glucocorticoid receptor agonists/antagonists, for urothelial carcinoma.
在晚期膀胱癌患者中，常给予糖皮质激素以减轻化疗过程中的急性毒性，尤其是恶心，以及改善恶病质状况。然而，糖皮质激素是否通过糖皮质激素受体途径直接影响膀胱癌的发展和进展仍不清楚。首先在人膀胱癌系和组织微阵列中研究了糖皮质激素受体的表达。然后，在膀胱癌系中检查了地塞米松对糖皮质激素受体转录、细胞增殖、凋亡/细胞周期和侵袭的影响。最后，使用膀胱癌小鼠异种移植模型评估地塞米松对肿瘤进展的疗效。检查的所有细胞系和组织均表达糖皮质激素受体。地塞米松增加了糖皮质激素受体介导的报告基因活性和细胞增殖，并在存在或不存在顺铂的情况下抑制凋亡。相反，地塞米松抑制细胞侵袭、其相关基因 [MMP-2/MMP-9、白细胞介素 (IL)-6、VEGF] 的表达以及 MMP-2/MMP-9 的活性，并诱导上皮间质转化。此外，地塞米松增加了 IκBα 蛋白水平和 NF-κB 的细胞质积累。在荷瘤小鼠中，地塞米松略微增加了接种肿瘤的生长，但完全阻止了血性腹水的发展，提示肿瘤细胞腹膜扩散和实际转移。在所有这些检测中，糖皮质激素受体拮抗剂或通过 RNA 干扰的糖皮质激素受体敲低均可消除地塞米松的作用。因此，糖皮质激素受体的激活通过抑制凋亡促进了细胞增殖，但抑制了细胞侵袭和转移。这些结果可能为开发改良的化疗方案提供基础，包括或不包括尿路上皮癌的糖皮质激素受体激动剂/拮抗剂。
