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Abstract
NR6A1/CT150, as an orphan receptor, is a novel member of the cancer-testis (CT) antigen family. Here, we investigated the expression and function of NR6A1 and its underlying mechanisms in prostate cancer (PCa) patients who underwent radical prostatectomy. A total of 303 cases of prostate cancer after radical prostatectomy were analysed in a tissue microarray (TMA) for NR6A1 immunohistochemistry-based protein expression. Kaplan–Meier/log-rank analysis and Cox regression analysis were used to investigate the relationship between NR6A1 expression and clinicopathological factors in PCa. NR6A1 mRNA expression was examined by reversing transcriptase-polymerase chain reaction (RT-PCR). Knockdown of NR6A1 by small interfering RNA mediated gene silencing and overexpression of NR6A1 through lentivirus were utilized to investigate its potential role in prostate cancer cells. NR6A1 protein expression was 29.7% (90/303) and mRNA expression was 28.1%(9/32) in PCa patients. NR6A1 expression was significantly associated with Gleason score (GS) (P=0.003) and tumor stage (P=0.042). The patients with positive NR6A1 expression have a shorter biochemical recurrence-free survival. NR6A1 predicted biochemical recurrence in univariate (P=0.0159) and multivariate models (P=0.0317). In addition, gene silencing of NR6A1 resulted in G0/G1 phase cell cycle arrest, and decreased metastatic and invasive potential of prostate cancer cells DU145 and PC3. In contrast, overexpression of NR6A1 reduced G0/G1 phase cell cycle arrest, and promoted metastatic and invasive potential of prostate cancer cells 22RV1. And overexpression of NR6A1 significantly promoted tumor growth in vivo. What's more, down regulation of NR6A1 could reverse epithelial-to-mesenchymal transition (EMT) process in DU145 and PC3 cell lines, and the overexpression could enhance EMT process in 22RV1 cell line. NR6A1 played a prominent role in migration and invasion of PCa cells, and it is indicated that NR6A1 may act as a novel marker for biochemical recurrence after radical prostatectomy.
Highlights
Prostate cancer (PCa) is one of the most commonly diagnosed cancers worldwide in men and the second cause of cancer-associated mortality in American men [1]
The aim of this study is to indicate that NR6A1 is a positive regulator of prostate cancer progression
Our results demonstrated that NR6A1 expression could be an important prognostic indicator for biochemical recurrence of patients with PCa after radical prostatectomy
Summary
Prostate cancer (PCa) is one of the most commonly diagnosed cancers worldwide in men and the second cause of cancer-associated mortality in American men [1]. NR6A1 may act as a transcriptional repressor that plays an important role in mouse embryonic development [10]. It is differentially regulated during retinoid-induced differentiation of embryonal carcinoma and embryonic stem cells [11, 12]. It has been reported that NR6A1 is lower expressed in ER+ and ER- breast cancer compared with normal mammary gland tissue, and low levels of NR6A1 in cancer cells exhibit higher sensitivity to the anticancer drug ecteinascidin[13]. Increased NR6A1 immunoreactivity was significantly associated with disease progression in PCa [14]. This gene may act as a promising biomarker of PCa aggressiveness
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