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.
Highlights
Urinary bladder cancer remains one of the most commonly diagnosed malignancies worldwide, especially in elderly men [1]
We first examined the expression of ZKSCAN3 in human bladder cancer cell lines, UMUC3, 647V, and 5637, as well as an immortalized human normal urothelial cell line, SVHUC, by western blotting (Figure 1A) and reverse transcription (RT)-polymerase chain reaction (PCR) (Figure 1B)
We have demonstrated that ZKSCAN3 expression is elevated in www.impactjournals.com/oncotarget bladder cancer, compared with non-neoplastic urothelium, and that ZKSCAN3 silencing results in inhibition of bladder cancer cell proliferation, migration, and invasion
Summary
Urinary bladder cancer remains one of the most commonly diagnosed malignancies worldwide, especially in elderly men [1]. More than two-thirds of newly diagnosed bladder tumors are superficial/non-muscleinvasive, which can typically be managed in a conservative manner These patients with superficial disease are at high risk of recurrence, with occasional stage progression, after transurethral resection of the tumor and currently available prophylactic intravesical therapy. ZKSCAN3 has been implicated in promoting the progression of a few types of malignancies, including colon cancer [5], multiple myeloma [6], and prostate cancer [7]. These malignancies have been found to overexpress ZKSCAN3 [5,6,7]. ZKSCAN3 has been shown to play a critical role in transcriptional regulation of autophagy [9, 10]
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