ZKSCAN3 promotes bladder cancer cell proliferation, migration, and invasion

Abstract

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.

ZKSCAN3 expression in urothelial carcinoma of the upper urinary tract and its impact on patient outcomes

“…We previously showed, in bladder specimens using [6]. In contrast to these previous findings, the levels of ZKSCAN3 expression was found to be considerably lower in UUTUCs than in non-neoplastic urothelial tissues.…”

“…In contrast to these previous findings, the levels of ZKSCAN3 expression was found to be considerably lower in UUTUCs than in non-neoplastic urothelial tissues. However, the status of ZKSCAN3 expression in benign urothelium from nephroureterectomy specimens appeared to be similar to that from bladder specimens in our previous study [6]. In addition, these normal-appearing tissues used for previous and current immunohistochemical stains were from surgical specimens from patients with bladder cancer and UUTUC, respectively, and therefore may not represent completely normal controls.…”

“…Recently, we demonstrated that ZKSCAN3 knockdown in bladder cancer lines resulted in considerable decreases in cell viability, along with increased apoptosis, as well as in cell migration and invasion [6]. Additionally, in xenograft-bearing mice, ZKSCAN3 knockdown significantly delayed tumor formation and subsequent tumor growth [6]. Thus, ZKSCAN3 activation appeared to contribute to the promotion of tumor progression in several types nephroureterectomy specimens.…”

“…It has indeed been documented that overexpression or gene amplification of ZKSCAN3 in tissue specimens correlates with colorectal cancer invasion [4] or prostate cancer metastasis [4], respectively. Recently, we demonstrated that ZKSCAN3 knockdown in bladder cancer lines resulted in considerable decreases in cell viability, along with increased apoptosis, as well as in cell migration and invasion [6]. Additionally, in xenograft-bearing mice, ZKSCAN3 knockdown significantly delayed tumor formation and subsequent tumor growth [6].…”

“…ZKSCAN3, a family member of the KRAB and SCAN domaincontaining zinc-finger transcription factors, has been shown to involve the outgrowth of malignancies [3][4][5][6]. It has indeed been documented that overexpression or gene amplification of ZKSCAN3 in tissue specimens correlates with colorectal cancer invasion [4] or prostate cancer metastasis [4], respectively.…”