Using preclinical models, we have recently found that ELK1, a transcriptional factor that activates downstream targets, includingc-fosproto-oncogene, induces bladder cancer outgrowth. Here, we immunohistochemically determined the expression status of phospho-ELK1, an activated form of ELK1, in upper urinary tract urothelial carcinoma (UUTUC). Overall, phospho-ELK1 was positive in 47 (47.5%; 37 weak (1+) and 10 moderate (2+)) of 99 UUTUCs, which was significantly (P= 0.002) higher than in benign urothelium (21 (25.3%) of 83; 17 1+ and 4 2+) and was also associated with androgen receptor expression (P= 0.001). Thirteen (35.1%) of 37 non-muscle-invasive versus 34 (54.8%) of 62 muscle-invasive UUTUCs (P= 0.065) were immunoreactive for phospho-ELK1. Lymphovascular invasion was significantly (P= 0.014) more often seen in phospho-ELK1(2+) tumors (80.0%) than in phospho-ELK1(0/1+) tumors (36.0%). There were no statistically significant associations between phospho-ELK1 expression and tumor grade, presence of concurrent carcinoma in situ or hydronephrosis, or pN status. Kaplan-Meier and log-rank tests revealed that patients with phospho-ELK1(2+) tumor had marginally and significantly higher risks of disease progression (P= 0.055) and cancer-specific mortality (P= 0.008), respectively, compared to those with phospho-ELK1(0/1+) tumor. The current results thus support our previous observations in bladder cancer and further suggest that phospho-ELK1 overexpression serves as a predictor of poor prognosis in patients with UUTUC.
International journal of molecular sciences. 2018 Mar 08*** epublish ***
Satoshi Inoue, Hiroki Ide, Kazutoshi Fujita, Taichi Mizushima, Guiyang Jiang, Takashi Kawahara, Seiji Yamaguchi, Hiroaki Fushimi, Norio Nonomura, Hiroshi Miyamoto
Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA. inosts411@gmail.com., Department of Pathology and James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. h-ide@fc4.so-net.ne.jp., Department of Urology, Osaka University Graduate School of Medicine, Suita 565-0871, Japan. fujita@uro.med.osaka-u.ac.jp., Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA. mizu123shima@gmail.com., Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA. guiyang_jiang@urmc.rochester.edu., Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA. takashi_tk2001@yahoo.co.jp., Department of Urology, Osaka General Medical Center, Osaka 558-8558, Japan. yamabu1956@gmail.com., Department of Pathology, Osaka General Medical Center, Osaka 558-8558, Japan. hiroaki-fushimi@gh.opho.jp., Department of Urology, Osaka University Graduate School of Medicine, Suita 565-0871, Japan. nono@uro.med.osaka-u.ac.jp., Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA. hiroshi_miyamoto@urmc.rochester.edu.