Izumi Koji, Inoue Satoshi, Ide Hiroki, Fujita Kazutoshi, Mizushima Taichi, Jiang Guiyang, Yamaguchi Seiji, Fushimi Hiroaki, Nonomura Norio, Miyamoto Hiroshi
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA.
Department of Urology and Renal Transplantation, Yokohama City University Medical Center, Yokohama, Japan.
Int J Urol. 2018 May;25(5):429-435. doi: 10.1111/iju.13528. Epub 2018 Feb 14.
To determine the expression status of uridine 5'diphospho-glucuronosyltransferase 1A, a major phase II drug metabolism enzyme, in upper urinary tract urothelial carcinoma, as well as to assess its prognostic significance.
We immunohistochemically stained for uridine 5'diphospho-glucuronosyltransferase 1A in tissue microarray consisting of 99 upper urinary tract urothelial carcinoma samples and paired non-neoplastic urothelial tissues. We also assessed the effect of uridine 5'diphospho-glucuronosyltransferase 1A knockdown on urothelial cancer cell growth.
Uridine 5'diphospho-glucuronosyltransferase 1A was positive in 92.9% (27.3% weak [1+], 37.4% moderate [2+], 28.3% strong [3+]) of tumors, which was significantly (P < 0.001) lower than in benign urothelial tissues (98.8%; 3.5% 1+, 18.8% 2+, 76.4% 3+). All 37 (100%) non-muscle-invasive versus 55 (88.7%) of 62 muscle-invasive tumors (P = 0.043) were immunoreactive for uridine 5'diphospho-glucuronosyltransferase 1A. The rates of moderate-to-strong uridine 5'diphospho-glucuronosyltransferase 1A expression and its positivity were also strongly associated with the absence of concomitant carcinoma in situ (P = 0.034) and lymphovascular invasion (P = 0.016), respectively. However, there were no statistically significant associations between uridine 5'diphospho-glucuronosyltransferase 1A expression and tumor grade or pN/M status. Uridine 5'diphospho-glucuronosyltransferase 1A loss in M0 tumors was strongly associated with lower progression-free survival (P < 0.001) and cancer-specific survival (P < 0.001) rates. Multivariate analysis further identified a strong correlation of uridine 5'diphospho-glucuronosyltransferase 1A positivity with reduced cancer-specific mortality (hazard ratio 0.28, P = 0.018). Meanwhile, uridine 5'diphospho-glucuronosyltransferase 1A knockdown in urothelial cancer cells resulted in significant increases in their viability and migration.
These results suggest a preventive role of uridine 5'diphospho-glucuronosyltransferase 1A signals in the development and progression of upper urinary tract urothelial carcinoma. Loss of uridine 5'diphospho-glucuronosyltransferase 1A expression might serve as an independent predictor of poor prognosis in patients with upper urinary tract urothelial carcinoma.
确定尿苷5'-二磷酸葡萄糖醛酸基转移酶1A（一种主要的II期药物代谢酶）在上尿路尿路上皮癌中的表达状态，并评估其预后意义。
我们对包含99例上尿路尿路上皮癌样本及配对的非肿瘤性尿路上皮组织的组织芯片进行尿苷5'-二磷酸葡萄糖醛酸基转移酶1A的免疫组化染色。我们还评估了尿苷5'-二磷酸葡萄糖醛酸基转移酶1A敲低对膀胱癌细胞生长的影响。
尿苷5'-二磷酸葡萄糖醛酸基转移酶1A在92.9%的肿瘤中呈阳性（27.3%为弱阳性[1+]，37.4%为中度阳性[2+]，28.3%为强阳性[3+]），显著低于良性尿路上皮组织（98.8%；3.5%为1+，18.8%为2+，76.4%为3+，P<0.001）。37例（100%）非肌层浸润性肿瘤与62例肌层浸润性肿瘤中的55例（88.7%）对尿苷5'-二磷酸葡萄糖醛酸基转移酶1A呈免疫反应（P=0.043）。尿苷5'-二磷酸葡萄糖醛酸基转移酶1A中度至强表达率及其阳性率也分别与无原位癌（P=0.034）和淋巴管浸润（P=0.016）密切相关。然而，尿苷5'-二磷酸葡萄糖醛酸基转移酶1A表达与肿瘤分级或pN/M状态之间无统计学显著关联。M0肿瘤中尿苷5'-二磷酸葡萄糖醛酸基转移酶1A缺失与无进展生存期（P<0.001）和癌症特异性生存期（P<0.001）降低密切相关。多因素分析进一步确定尿苷5'-二磷酸葡萄糖醛酸基转移酶1A阳性与癌症特异性死亡率降低密切相关（风险比0.28，P=0.018）。同时，尿路上皮癌细胞中尿苷5'-二磷酸葡萄糖醛酸基转移酶1A敲低导致其活力和迁移显著增加。
这些结果提示尿苷5'-二磷酸葡萄糖醛酸基转移酶1A信号在上尿路尿路上皮癌发生和进展中具有预防作用。尿苷5'-二磷酸葡萄糖醛酸基转移酶1A表达缺失可能是上尿路尿路上皮癌患者预后不良的独立预测指标。
