PDF file - 5939K, The expression of GR in human BC. A, GR mRNA expression was analyzed in UMUC3, TCC-SUP, J82, and 5637 cells by RT-PCR, and transcripts (163 bp) were separated on an agarose gel. PCR products derived from GAPDH mRNA (71 bp) served as an internal control. B, Cell extracts from UMUC3, TCC-SUP, J82, and 5637 were analyzed on western blotting, using an antibody to GR (95 kDa, with a second band at 90 kDa). β-Actin protein (43 kDa) served as an internal control. C, Immunohistochemistry (IHC) of GR in bladder TMA, including benign urothelium, primary urothelial carcinoma, and lymph node (LN) metastasis. The Kaplan-Meier analysis was performed to assess progression-free survival in patients with BC, according to the levels of GR expression. Comparison was made by log-rank test. Tumor progression was defined as development of local recurrence or metastatic tumor.
ARTICLE ABSTRACT
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. Mol Cancer Ther; 11(12); 2621–32. ©2012 AACR.
