NFATc1 Expression as a Prognosticator in Urothelial Carcinoma of the Upper Urinary Tract

Abstract

We recently found that NFATc1, a member of the NFAT family and a key regulator of the immune response, could induce bladder carcinogenesis and cancer progression. In this study, we immunohistochemically stained for NFATc1 in upper urinary tract urothelial carcinoma (UUTUC) specimens and paired nonneoplastic urothelial tissues. NFATc1 was positive in 51 [52%; 40 (40%) weak (1+), 9 (9%) moderate (2+), and 2 (2%) strong (3+)] of 99 UUTUCs, which was significantly higher than in benign urothelium [30 (36%) of 83; 28 (34%) weak and 2 (2%) moderate] (0 vs 1+/2+/3+, P = .038; 0/1+ vs 2+/3+, P = .023). There were no significant associations between NFATc1 expression pattern and tumor grade or pT stage. However, the positive rates of NFATc1 expression tended to be higher in renal pelvic tumors (60%) than in ureteral tumors (42%; P = .080) as well as in pN+ tumors (75%) than in pN0 tumors (49%; P = .089). Kaplan-Meier and log-rank tests revealed that moderate (2+) to strong (3+) NFATc1 expression correlated with lower progression-free survival (P = .032) and cancer-specific survival (P = .005) rates in the 99 cases. Patients with high (2+/3+) NFATc1 muscle-invasive tumor (n = 9) also had a significantly higher risk of cancer-specific mortality (P = .021) compared to those with low (0/1+) NFATc1 muscle-invasive tumor (n = 53). Thus, compared with nonneoplastic urothelium, a significant increase in the expression of NFATc1 in UUTUC was seen, implying the involvement of NFATc1 signals in the development of UUTUC. The current results further suggest that NFATc1 overexpression serves as a predictor of poor prognosis in patients with UUTUC.

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

“…8 In UUTUC, however, UGT1A expression inversely correlated only with pT stage, but not tumor grade. 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 Wound-healing assay in UMUC3-control-siRNA versus UMUC3-UGT1A-siRNA. Loss or weak expression of UGT1A was also associated with the presence of other known prognostic factors, such as lymphovascular invasion and concomitant CIS, but not lymph node metastasis or hydronephrosis.…”

“…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. 16,17,23 Another possibility includes a higher proportion of superficial disease (pTa or pT1), where UGT1A expression is more likely strong, in RPTs (44.4%) compared with UTs (34.0%). Furthermore, we previously found that UGT1A was lost in three metastatic urothelial tumors in the lymph node, and was weakly positive (1+) in the other three tumors (unpubl.…”

“…Using the same set of TMA, we recently showed marginal increases (P = 0.080) in the positivity of a transcription factor, NFATc1, which was shown to promote urothelial tumorigenesis and tumor progression, 23,24 in RPTs (60.0%) compared with UTs (42.0%). 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.…”

“…15 Appropriate approval was obtained from the institutional review board before construction and use of the TMA. 15,16 None of the patients had received therapy with radiation or anticancer drugs before the collection of the tissues included in the TMA. 15,16 None of the patients had received therapy with radiation or anticancer drugs before the collection of the tissues included in the TMA.…”

“…Clinicopathological data of these 99 patients described previously are shown in Table 1. 15,16 None of the patients had received therapy with radiation or anticancer drugs before the collection of the tissues included in the TMA.…”