Expression of UDP-Glucuronosyltransferase 1A (UGT1A) in Bladder Cancer: Association with Prognosis and Regulation by Estrogen
Koji Izumi, Yi Li, Hitoshi Ishiguro, Yichun Zheng, Jorge L Yao, George J Netto, Hiroshi Miyamoto. University of Rochester, Rochester, NY; Johns Hopkins Medical Institutions, Baltimore, MD
Background: UGT1A plays an important role in preventing bladder cancer initiation by detoxifying carcinogenic compounds. We recently showed down-regulation of UGT1A by androgens in non-neoplastic bladders. However, the role of UGT1A in bladder cancer progression is poorly understood. The purpose of this study is to investigate the relationship of UGT1A expression to tumor progression and signals of sex hormone receptors in urothelial cells.
Design: We immunohistochemically stained for UGT1A in bladder tissue microarrays where the expression of sex hormone receptors had been assessed. We then evaluated the association between UGT1A expression and clinicopathologic features available for our patient cohort. The expression of UGT1A/Ugt1a was also measured by quantitative real-time PCR in urothelial cell lines treated with sex hormones/the bladders from ovariectomized mice, respectively.
Results: UGT1A was positive in 130/145 [90%; 28 (19%) weak, 53 (37%) moderate, and 49 (34%) strong] urothelial neoplasms, which was significantly weaker than in matched non-neoplastic urothelial tissues [100/101 (99%); 2 (2%) weak, 17 (17%) moderate, and 81 (80%) strong]. Fifty (98%) of 51 low-grade/79 (99%) of 80 non-muscle-invasive tumors were immunoreactive to UGT1A, whereas 80 (85%) of 94 high-grade/51 (78%) of 65 muscle-invasive tumors were UGT1A-positive. Kaplan-Meier analysis showed strong associations between lower UGT1A expression versus the risk of recurrence in high-grade non-muscle-invasive tumors (P=0.038) or disease-specific mortality in muscle-invasive tumors (P=0.016). Multivariate analysis further revealed UGT1A loss as an independent prognosticator for disease-specific mortality in patients with muscle-invasive tumor (P=0.010). UGT1A expression was positively and negatively correlated with those of estrogen receptor (ER)-α and ER-β, respectively. In normal urothelium/bladder cancer lines, 17β-estradiol increased/decreased UGT1A expression, respectively, and an anti-estrogen abolished these effects. In contrast, dihydrotestosterone showed marginal effects on UGT1A in bladder cancer cells. Additionally, ovariectomy in mice resulted in down-regulation of Ugt1a subtypes.
Conclusions: Our results suggest the involvement of UGT1A in not only bladder carcinogenesis but tumor progression. Moreover, UGT1A is likely regulated by estrogens in non-neoplastic urothelium versus bladder tumor in opposite manners, which could be underlying mechanisms of gender-specific differences in bladder cancer incidence and progression.
Category: Genitourinary (including renal tumors)
Tuesday, March 5, 2013 9:30 AM
Poster Session III # 106, Tuesday Morning