Expression of Glucocorticoid Receptor and FOXO1/phospho-FOXO1 in Bladder Cancer as Independent Prognosticators.

BACKGROUND/AIM: Cross-talk between forkhead box O1 (FOXO1), a transcriptional factor known to function as a tumor suppressor via the PI3K/AKT pathway, and glucocorticoid receptor (GR) has been implied in non-urothelial cells. The present study aimed to investigate the association of FOXO1 and GR expression in bladder cancer and its prognostic significance.

MATERIALS AND

METHODS

Immunohistochemical staining for GR, FOXO1, and p-FOXO1 (a phosphorylated/inactivated form) was performed in a set of bladder cancer tissue microarray comprising 50 low-grade non-invasive tumors, 28 high-grade non-muscle-invasive tumors, and 51 high-grade muscle-invasive tumors. Western blotting for FOXO1 and p-FOXO1 was also conducted in human bladder cancer cells.

RESULTS

GR expression was detected in 109 [84.5%; 39 (30.2%) weakly positive (1+), 39 (30.2%) moderately positive (2+), 31 (24.0%) strongly positive (3+)] tumors, whereas FOXO1 and p-FOXO1 were immunoreactive in 17 [13.2%; 16 (12.4%) 1+, 1 (0.8%) 2+] and 71 [55.0%; 57 (44.2%) 1+, 14 (10.9%) 2+] tumors, respectively. The expression levels of GR were positively and negatively correlated with those of FOXO1 (p=0.003) and p-FOXO1 (p=0.009), respectively. GR(0/1+)/FOXO1(0) and GR(0/1+)/p-FOXO1(1+/2+) were significantly more often observed in high-grade (vs. low-grade) or muscle-invasive (vs. non-muscle-invasive) tumors. Both univariate and multivariate analyses revealed that GR(0/1+)/FOXO1(0) and GR(0/1+)/p-FOXO1(1+/2+) were associated with a significantly higher risk for the recurrence of non-invasive disease or progression of muscle-invasive disease. In 2 GR-positive bladder cancer lines, glucocorticoids (i.e., dexamethasone, prednisone) and a GR antagonist (i.e., RU486) induced the levels of FOXO1 and p-FOXO1 expression, respectively.

CONCLUSION

The expression levels of GR and FOXO1 or p-FOXO1 were strongly correlated in bladder cancer. Specific GR/FOXO1 and GR/p-FOXO1 expression profiles served as independent predictors of disease recurrence or progression.