ZKSCAN3 promotes bladder cancer cell proliferation, migration, and invasion
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Takashi Kawahara1,2,3,*, Satoshi Inoue1,*, Hiroki Ide1, Eiji Kashiwagi1, Shinji Ohtake3, Taichi Mizushima1, Peng Li1, Yi Li2, Yichun Zheng1,2, Hiroji Uemura3, George J. Netto1, Hitoshi Ishiguro1,2, Hiroshi Miyamoto1,2
1Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
2Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
3Departments of Urology and Renal Transplantation, Yokohama City University Medical Center, Yokohama, Japan
*These authors have contributed equally to this work
Hiroshi Miyamoto, email: firstname.lastname@example.org
Keywords: bladder cancer, immunohistochemistry, tumor progression, ZKSCAN3
Received: March 08, 2016 Accepted: July 09, 2016 Published: July 18, 2016
The expression status of ZKSCAN3, a zinc-finger transcription factor containing KRAB and SCAN domains, as well as its biological significance, in human bladder cancer remains largely unknown. In the current study, we aimed to determine the functional role of ZKSCAN3 in bladder cancer progression. Immunohistochemistry in tissue specimens detected ZKSCAN3 signals in 138 (93.2%) of 148 urothelial neoplasms, which was significantly higher than in non-neoplastic urothelial tissues [76 (84.4%) of 90; P=0.044]. Correspondingly, the levels of ZKSCAN3 gene were significantly elevated in bladder tumors, compared with those in adjacent normal-appearing bladder mucosae (P=0.008). In a validation set of tissue microarray, significantly higher ZKSCAN3 expression was observed in high-grade and/or muscle-invasive urothelial carcinomas than in low-grade and/or non-muscle-invasive tumors. Two bladder cancer cell lines, UMUC3 and 647V, were found to strongly express ZKSCAN3 protein/mRNA, whereas its expression in 5637 bladder cancer and SVHUC normal urothelium cell lines was very weak. ZKSCAN3 silencing via its short hairpin RNA (shRNA) in UMUC3 and 647V resulted in significant decreases in cell viability/colony formation, cell migration/invasion, and the expression of matrix metalloproteinase (MMP)-2/MMP-9 and oncogenes c-myc/FGFR3, as well as significant increases in apoptosis and the expression of tumor suppressor genes p53/PTEN. ZKSCAN3 overexpression in 5637 also induced cell growth and migration. In addition, ZKSCAN3-shRNA expression considerably retarded tumor formation as well as its subsequent growth in xenograft-bearing mice. These results suggest that ZKSCAN3 plays an important role in bladder cancer outgrowth. Thus, ZKSCAN3 inhibition has the potential of being a therapeutic approach for bladder cancer.
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