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

Shobeiri, S. Abbās; Inoue, Satoshi; Fujita, Kazutoshi; Ide, Hiroki; Mizushima, Taichi; Yamaguchi, Seiji; Fushimi, Hiroaki; Nonomura, Norio; Miyamoto, Hiroshi

doi:10.15761/icst.1000241

Cited by 3 publications

(4 citation statements)

References 11 publications

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“…Using immunohistochemistry in the same sets of UUTUC and bladder cancer TMAs, we have assessed the expression of various proteins. Interestingly, renal pelvic tumors, compared with ureteral tumors, exhibited lower positive rates of five (out of seven) transcription factors, including AR (11.1% vs. 28.0%, P = 0.070) [ 14 ], ERβ (51.1% vs. 72.0%, P = 0.056) [ 14 ], GR (57.8% vs. 68.0%, P > 0.1) [ 14 ], GATA3 (35.6% vs. 66.0%, P = 0.004) [ 18 ], and ZKSCAN3 (26.7% vs. 54.0%, P = 0.012) [ 19 ]. The expression of all of these transcription factors (except ERβ), in addition to p-ELK1, was further up-regulated in bladder tumors, compared with ureteral tumors [ 20 , 21 , 22 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

Expression of Phospho-ELK1 and Its Prognostic Significance in Urothelial Carcinoma of the Upper Urinary Tract

Inoue

Ide

Fujita

et al. 2018

IJMS

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Using preclinical models, we have recently found that ELK1, a transcriptional factor that activates downstream targets, including c-fos proto-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.

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Section: Discussionmentioning

confidence: 99%

Expression of Phospho-ELK1 and Its Prognostic Significance in Urothelial Carcinoma of the Upper Urinary Tract

Inoue

Ide

Fujita

et al. 2018

IJMS

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“…Using the identical UUTUC TMA, we previously determined the expression status of various transcription factors (20,(23)(24)(25)(26). Notably, the positive rates of 6 transcription factors, including AR (20), ERβ (20), GATA-binding protein 3 (GATA3) (23), zinc finger with KRAB and SCAN domains 3 (ZKSCAN3) (24), nuclear factor of activated T-cells 1 (NFATc1) (25) and a phosphorylated form of ELK1 (p-ELK1) (26), were significantly (P<0.05; GATA3, ZKSCAN3) or insignificantly (0.05≤P<0.1; AR, ERβ, NFATc1, p-ELK1) different between renal pelvic and ureteral tumor samples, although the underlying reasons remain unclear. However, similar to other transcription factors previously examined, including ERα (20), GR (20) and PR (20), no significant change (P≥0.1) in the levels of p-FOXO1 expression at different sites of UUTUC was identified in the present study.…”

Section: Discussionmentioning

confidence: 99%

Forkhead box O1 as an indicator of prognosis is inactivated in urothelial carcinoma of the upper urinary tract

et al. 2018

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The transcription factor forkhead box O1 (FOXO1) can be inactivated via its phosphorylation, resulting in suppression of apoptosis. Using immunohistochemistry, the expression of a phosphorylated form of FOXO1 was assessed in upper urinary tract urothelial carcinoma (UUTUC) specimens. Overall, phospho-FOXO1 (p-FOXO1) was immunoreactive in all 99 UUTUC specimens [12 (12.1%) weak (1+), 46 (46.5%) moderate (2+) and 41 (41.4%) strong (3+)], which was significantly (P= 0.018) increased, compared with benign urothelium specimens [77/82 (93.9%): 18 (22.0%) 1+, 41 (50.0%) 2+ and 18 (22.0%) 3+]. Muscle invasion (P= 0.031) and lymphovascular invasion (P= 0.025) were observed more frequently in p-FOXO1(2+/3+) tumor samples compared with p-FOXO1(1+) tumor samples. No statistically significant associations between p-FOXO1 expression and tumor grade or presence of concurrent carcinoma in situ, hydronephrosis or lymph node metastasis were observed. Furthermore, the levels of p-FOXO1 and estrogen receptor-β expression were significantly (P<0.05) correlated in UUTUC samples [correlation coefficient (CC)= 0.244], particularly in tumor samples from male patients (CC= 0.330). Additionally, patients with p-FOXO1(3+) tumors had a significantly increased risk of cancer-specific mortality (P= 0.043), compared with those with p-FOXO1(1+/2+) tumors. Multivariate analysis further demonstrated a notable, albeit not significant, association between p-FOXO1 expression and cancer-specific survival (hazard ratio=2.204; P=0.053). These findings indicate that FOXO1 is inactivated in UUTUC specimens and p-FOXO1 overexpression may serve as a predictor of poor patient outcomes.

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“…A relatively small number of the patients with low-grade tumor (n = 15) in the current study might be a reason for this discrepancy. 30 Thus, the expression patterns of these transcription factors are not well correlated with their functional roles (e.g. Meanwhile, it was recently documented, in colon cancer lines, that knockdown of UGT1A resulted in an increase in cell proliferation through p53 inactivation, suggesting its function as a suppressor of tumor progression in addition to tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

“…16 In contrast, in our recent studies, RPTs showed lower positive rates of other transcription factors, such as androgen receptor known to promote urothelial tumor outgrowth 7,25 (11.1% vs 28.0%, P = 0.070), 17 estrogen receptorb that could inhibit urothelial tumor outgrowth 8,25 (51.1% vs 72.0%, P = 0.056), 17 GATA3 shown to function as a tumor suppressor 26,27 (35.6% vs 66.0%, P = 0.004) 28 and ZKSCAN3 shown to function as an oncogene 29 (26.7% vs 54.0%, P = 0.012). 30 Thus, the expression patterns of these transcription factors are not well correlated with their functional roles (e.g. tumor suppressor vs oncogene).…”

Section: Discussionmentioning

confidence: 99%

Uridine 5'diphospho‐glucuronosyltransferase 1A expression as an independent prognosticator in urothelial carcinoma of the upper urinary tract

et al. 2018

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

Cited by 3 publications

References 11 publications

Expression of Phospho-ELK1 and Its Prognostic Significance in Urothelial Carcinoma of the Upper Urinary Tract

Expression of Phospho-ELK1 and Its Prognostic Significance in Urothelial Carcinoma of the Upper Urinary Tract

Forkhead box O1 as an indicator of prognosis is inactivated in urothelial carcinoma of the upper urinary tract

Uridine 5'diphospho‐glucuronosyltransferase 1A expression as an independent prognosticator in urothelial carcinoma of the upper urinary tract

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