MP88-06 NUCLEAR FACTOR (NF)-κB SIGNALS PROMOTE UROTHELIAL TUMORIGENESIS THROUGH THE ANDROGEN RECEPTOR (AR) PATHWAY (2017)

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology IV1 Apr 2017MP88-06 NUCLEAR FACTOR (NF)-κB SIGNALS PROMOTE UROTHELIAL TUMORIGENESIS THROUGH THE ANDROGEN RECEPTOR (AR) PATHWAY Hiroki Ide, Satoshi Inoue, Taichi Mizushima, Mototsugu Oya, George Netto, and Hiroshi Miyamoto Hiroki IdeHiroki Ide More articles by this author , Satoshi InoueSatoshi Inoue More articles by this author , Taichi MizushimaTaichi Mizushima More articles by this author , Mototsugu OyaMototsugu Oya 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.2017.02.2731AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Emerging preclinical evidence has indicated the involvement of AR signaling in urothelial tumorigenesis. Meanwhile, cross-talk between AR and NF-κB, a protein complex of transcriptional factor and its phosphorylation is required for optimal induction of target genes, has been demonstrated in prostate cancer cells. We therefore investigated the role of NF-κB in neoplastic transformation of urothelial cells in relation to AR signaling. METHODS We immunohistochemically stained for NF-κB and phospho-NF-κB (p-NF-κB) in 149 bladder tumor and paired non-neoplastic bladder tissue specimens. Then, in immortalized human normal urothelial SVHUC sublines stably expressing AR with exposure to a chemical carcinogen 3-methylcholanthrene (MCA), we assessed the effects of NF-κB activator (betulinic acid; BA) and inhibitor (parthenolide; PAR) on the expression of AR, NF-κB p65 subunit, oncogenes, and tumor suppressors (via RT-PCR or western blot) as well as neoplastic transformation (via cell viability assay and plate/soft agar colony formation assays). Finally, N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was given to male C57BL/6 mice to induce bladder tumors. RESULTS NF-?B and p-NF-?B were positive in 100% [9% weak (1+), 40% moderate (2+), 51% strong (3+)] and 69% (44% 1+, 24% 2+, 1% 3+) of tumors, which was significantly elevated compared with non-neoplastic urothelial tissues [100% (25% 1+, 40% 2+, 35% 3+), P=0.016 (0/1+/2+ vs. 3+); and 46% (36% 1+, 10% 2+), p<0.001 (0 vs. 1+/2+/3+)]. Significantly higher rates of p-NF-κB positivity were also seen in high-grade (76%, P=0.015) or muscle-invasive (78%, P=0.033) tumors than in low-grade (56%) or non-muscle-invasive (62%) tumors. In SVHUC-AR cells, BA induced and PAR reduced the expression of p65 and AR. Notably, BA accelerated and PAR prevented neoplastic transformation of MCA-SVHUC-AR cells, but not that of MCA-SVHUC cells. Additionally, in MCA-SVHUC-AR cells, BA up-regulated the expression of c-myc and down-regulated that of p53, p21, and UGT1A, while PAR showed the opposite results. Moreover, bladder tumors were identified in 56% (mock), 89% (BA), and 22% (PAR) of BBN-treated mice sacrificed at 21 weeks of age. CONCLUSIONS Compared with non-neoplastic urothelium, NF-κB appeared to be activated in bladder cancer. In addition, NF-κB modulators were found to involve the regulation of tumorigenesis in AR-activated urothelial cells. Accordingly, NF-κB inhibition, together with AR inactivation, has the potential of being an effective chemopreventive approach for urothelial carcinoma. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1176 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Hiroki Ide More articles by this author Satoshi Inoue More articles by this author Taichi Mizushima More articles by this author Mototsugu Oya 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 ...