Cytoplasmic mislocalization of the orphan nuclear receptor Nurr1 is a prognostic factor in bladder cancer

Abstract

Nurr1 belongs to a novel class of orphan nuclear receptors (the NR4A family). The authors have previously shown that Nurr1 is important in carcinogenesis. In the current study, they examined the clinicopathologic relevance of expression patterns of Nurr1 in bladder tumors. Nurr1 expression was determined using immunohistochemical staining in a bladder cancer tissue array (145 tumors). Tumors were classified according to Nurr1 protein levels in both cytoplasm and nucleus. Disease-specific survival and recurrence-free survival were investigated by Kaplan-Meier analysis and Cox proportional hazards analysis in multivariate models and correlated with variables such as tumor stage, growth pattern, and clinical outcome (recurrence and survival). In vitro, Nurr1 was examined for its role in bladder cancer cell proliferation and migration using small interfering RNA silencing. Nurr1 expression in tumor cells correlated with increasing tumor stage and invasive growth pattern. Disease-specific survival was significantly shorter in patients whose tumors demonstrated a high level of cytoplasmic Nurr1 compared with those with lower levels of cytoplasmic Nurr1 expression. Furthermore, cytoplasmic Nurr1 expression level was found to be an independent predictor of disease-specific survival (odds ratio, 4.894; P < .001). In vitro, silencing of endogenous Nurr1 attenuated the migration of bladder cancer cells. The expression of Nurr1 in the cytoplasm correlates with adverse outcome and is an independent prognostic marker for tumor progression and survival in patients with bladder cancer. This might represent a novel target in bladder cancer therapy.