The enhanced expression of estrogen-related receptor α in human bladder cancer tissues and the effects of estrogen-related receptor α knockdown on bladder cancer cells

Estrogen-related receptor alpha (ERR alpha) belongs to the superfamily of nuclear orphan receptors. However, the role of ERR alpha in bladder cancer remains unknown. This study examined the expression of ERR alpha in bladder cancer tissues and explored the molecular mechanisms of ERR alpha in bladder cancer progression. The expression of ERR alpha in bladder cancer tissues from 61 patients was determined by immunohistochemistry. We performed quantitative real-time polymerase chain reaction assay to detect the gene expression levels and carried out Western blot assay to measure protein levels. In vitro functional assays, including colony formation, Cell Counting Kit-8, Transwell invasion, and migration assays, were performed to detect bladder cancer cell growth, proliferation, invasion, and migration, respectively. Flow cytometry was used to determine the cell apoptotic rate of bladder cancer cells. Among the 61 detected bladder cancer tissues, 39 bladder cancer tissues showed positive ERR alpha immunoreactivity. Higher ERR alpha immunoreactivity score was significantly associated with TNM stage, tumor grade, distant metastasis, and poor survival in patients with bladder cancer. Univariate and multivariate analyses showed that ERR alpha immunoreactivity was an independent prognostic factor for overall survival in patients with bladder cancer. ERR alpha was found to be upregulated in bladder cancer cell lines, and knockdown of ERR alpha suppressed bladder cancer cell growth, proliferation, invasion, and migration; promoted bladder cancer cell apoptosis; and inhibited the epithelial-mesenchymal transition of bladder cancer cells. On the other hand, bladder cancer cell proliferation, invasion, and migration were significantly enhanced after cells were transfected with an ERR alpha-overexpressing vector. In vivo tumor growth and metastasis assays showed that ERR alpha knockdown resulted in remarkable inhibition of tumor growth and tumor metastasis in nude mice. Collectively, our results suggest that the enhanced expression of ERR alpha may play a key role in the development and progression of bladder cancer and ERR alpha may serve as an important prognostic factor for bladder cancer.