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. ., Department of Pathology and James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. ., Department of Urology, Osaka University Graduate School of Medicine, Suita 565-0871, Japan. ., Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA. ., Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA. ., Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA. ., Department of Urology, Osaka General Medical Center, Osaka 558-8558, Japan. ., Department of Pathology, Osaka General Medical Center, Osaka 558-8558, Japan. ., Department of Urology, Osaka University Graduate School of Medicine, Suita 565-0871, Japan. ., Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA. .