MP83-18 FOXO1 AS A POTENTIAL TUMOR SUPPRESSOR IS INACTIVATED BY ANDROGENS IN BLADDER CANCER CELLS

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology IV1 Apr 2016MP83-18 FOXO1 AS A POTENTIAL TUMOR SUPPRESSOR IS INACTIVATED BY ANDROGENS IN BLADDER CANCER CELLS Hiroki Ide, Satoshi Inoue, Yi Li, Yichun Zheng, Eiji Kashiwagi, Takashi Kawahara, George Netto, and Hiroshi Miyamoto Hiroki IdeHiroki Ide More articles by this author , Satoshi InoueSatoshi Inoue More articles by this author , Yi LiYi Li More articles by this author , Yichun ZhengYichun Zheng More articles by this author , Eiji KashiwagiEiji Kashiwagi More articles by this author , Takashi KawaharaTakashi Kawahara More articles by this author , George NettoGeorge Netto More articles by this author , and Hiroshi MiyamotoHiroshi Miyamoto More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2200AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Little is known about the functional role of FOXO1, a transcriptional factor known to induce apoptosis through the PI3K-Akt pathway, in bladder cancer (BC). Meanwhile, preclinical evidence has suggested the involvement of androgen receptor (AR) signaling in BC progression. In this study, we aimed to determine the expression levels of FOXO1 and its inactive form, phospho-FOXO1 (p-FOXO1), as well as their correlations with AR signals in BC. METHODS We immunohistochemically stained for FOXO1/p-FOXO1 in 129 BC specimens. Using RT-PCR and western blot, we also assessed the expression of FOXO1/p-FOXO1 in AR-positive [e.g. UMUC3, 5637 or 647V stably expressing AR] and AR-negative (e.g. UMUC3-AR-short hairpin RNA, 5637, 647V) BC lines treated with androgens [e.g. dihydrotestosterone (DHT), R1881] and/or anti-androgens (e.g. flutamide, bicalutamide). RESULTS FOXO1/p-FOXO1 was positive in 13%/55% of BC tissues, which was significantly lower (40%; P < 0.001)/higher (24%; P < 0.001) than in non-neoplastic urothelial tissues. Twelve (24%) of 50 low-grade versus 5 (6%) of 79 high-grade BCs (P < 0.001) and 16 (21%) of 78 non-muscle-invasive versus 1 (2%) of 51 muscle-invasive BCs (P = 0.002) were immunoreactive for FOXO1. p-FOXO1 positivity in BCs was also significantly associated with lymph node metastasis (P = 0.020). In addition, there was a strong correlation between p-FOXO1 and AR expression (P = 0.031). Kaplan-Meier and log-rank tests revealed that patients with FOXO1-negative non-muscle-invasive (NMI) BC (P = 0.016) and p-FOXO1-positive muscle-invasive BC (P = 0.041) had significantly higher risks of recurrence and progresion, respectively. Multivariate analysis further identified FOXO1 expression as an independent predictor of the recurrence of NMI tumors (HR = 0.128; P = 0.043). Correspondingly, FOXO1 expression was considerably higher in AR-negative BC lines than in AR-positive lines. Moreover, androgen treatment reduced/induced the levels of FOXO1/p-FOXO1 expression, respectively, in AR-positive cells in a dose dependent manner. In these cells, antiandrogens abolished the effects of androgens on FOXO1/p-FOXO1 expression. CONCLUSIONS FOXO1 appears to be inactivated in BC, suggesting its preventive role in tumor outgrowth. FOXO1 loss or p-FOXO1 overexpression is also correlated with tumor recurrence or progression and may serve as a prognosticator of BC. Furthermore, FOXO1 activity appears to be regulated by AR signals. Accordingly, FOXO1 stimulation, together with AR inactivation, has the potential of being a chemopreventive or therapeutic approach for BC. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e1088 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Hiroki Ide More articles by this author Satoshi Inoue More articles by this author Yi Li More articles by this author Yichun Zheng More articles by this author Eiji Kashiwagi More articles by this author Takashi Kawahara More articles by this author George Netto More articles by this author Hiroshi Miyamoto More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...