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

Abstract

BACKGROUND: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.METHODS: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.RESULTS: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.CONCLUSIONS: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. Cancer 2010. © 2010 American Cancer Society.

Nuclear Import and Export Signals Control the Subcellular Localization of Nurr1 Protein in Response to Oxidative Stress*

“…mic localization of Nurr1 in glutamate-treated neurons (46). Moreover, it has been reported that Nurr1 exhibits a cytoplasmic localization in some bladder tumors (26). Although those studies did not explore the molecular mechanisms involved in nucleus-cytoplasm shuttling of Nurr1, they provide further evidence on pathological mechanisms that lead to the nuclear exclusion of Nurr1.…”

Expression of orphan nuclear receptor NR4A2 in gastric cancer cells confers chemoresistance and predicts an unfavorable postoperative survival of gastric cancer patients with chemotherapy

“…However, cytoplasmic mislocalization of NR4A2 has been related to a poor prognosis of bladder cancer. 29 The function of NR4A2 in different subcellular localization should be further elucidated. Because NR4A2 expression confers chemoresistance, the chemotherapy may select a subset of cancer cells with high NR4A2 expression, and these cancer cells might be major populations of cancer recurrence.…”

Orphan Nuclear Receptor Nurr1 as a Potential Novel Marker for Progression in Human Prostate Cancer

“…Some studies show oncogenic activities of Nurr1 in a cell type-specific manner (Ke et al, 2004;Holla et al, 2006;Li and Tai, 2009). There is also one study showing that the cytoplasmic mislocalization of Nurr1 protein is associated with cancer progression (Inamoto et al, 2010). No earlier studies have compared the actual expression of Nurr1 protein with prostate cancer stages and grades.…”

“…Recently, the oncogenic activities of Nurr1 are emerging. Nurr1 may stimulate progression of colorectal cancer by protecting cell survival (Holla et al, 2006), and induce suppression of apoptosis in cervical cancer cells (Ke et al, 2004), and is an independent prognostic marker for tumor progression and survival in patients with bladder cancer (Inamoto et al, 2010). To date, there have been no studies regarding the significance of Nurr1 expression in human prostate cancer.…”

“…As nontargeting control, Silencer Negative Control small interfering RNA (Ambion) was used (Inamoto et al, 2010). Cells were incubated to 60% -80% confluency in 6-well plates and transfected with specific or nonspecific small interfering RNA using siRNA Transfection Reagent (Santa Cruz Biotechnology, Santa Cruz, CA, USA) according to the manufacturer's instructions.…”