Expression of Snail in Upper Urinary Tract Urothelial Carcinoma: Prognostic Significance and Implications for Tumor Invasion
Expression of Snail in Upper Urinary Tract Urothelial Carcinoma: Prognostic Significance and Implications for Tumor Invasion
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DOI：
10.1158/1078-0432.ccr-10-0230
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发表时间：
2010-12-01
影响因子：
11.5
通讯作者：
Oya, Mototsugu
中科院分区：
文献类型：
--
作者：
Kosaka, Takeo;Kikuchi, Eiji;Oya, Mototsugu
目的：目前尚缺乏预测上尿路尿路上皮癌预后的分子标志物。Snail参与上皮-间质转化（EMT），在肿瘤进展中有报道，但在UTUC中尚不清楚。因此，我们解决了表达和生物学意义的蜗牛在UTUC。实验设计：为了阐明蜗牛在UTUC的生物学意义，我们研究了免疫组化表达的蜗牛在UTUC和分析其临床意义在150例UTUC患者。结果：浅表尿路上皮癌细胞核内Snail染色较弱;相反，在侵袭性UTUC的许多细胞核中观察到强烈的Snail染色。Snail表达在高肿瘤分期、高级别和显示淋巴管浸润（LVI）的肿瘤中显著较高。多变量考克斯回归分析显示，Snail表达升高是无复发生存率和癌症特异性生存率的显著和独立的预后预测因子。LVI阳性和Snail高表达的患者预后较差。用Snail特异性siRNA靶向UMUC-3细胞中Snail mRNA表达下调Snail、波形蛋白、MMP 2和MMP 9的mRNA表达。此外，与Snail的siRNA的细胞表现出较低的侵袭活性与非靶向siRNA.Conclusion转染的细胞相比：蜗牛诱导的EMT代表了临床相关的机制UTUC进展和一个有吸引力的目标，为治疗UTUC患者。临床癌症研究; 16（23）; 5814-23。（C）2010年AACR。
Purpose: There are few molecular markers known to predict upper urinary tract urothelial carcinomas (UTUC) prognosis. Snail, which contributes to epithelial-mesenchymal transition (EMT), has been documented in cancer progression, but not clear yet in UTUC. We therefore addressed the expression and biological significance of Snail in UTUC.Experimental Design: To elucidate the biological significance of Snail in UTUC, we examined the immunohistochemical expression of snail in UTUC and analyzed its clinical significance in 150 patients with UTUC. Biological effects of Snail in EMT and invasion were evaluated by using small interfering RNA (siRNA) specific for Snail in urothelial carcinoma cell lines and the Matrigel invasion assay.Results: Nuclear Snail staining was very weak in superficial UTUC. In contrast, strong Snail staining was observed in many of the nucleus of invasive UTUC. Snail expression was significantly higher in the high tumor stage, high grade, and in tumors showing lymphovascular invasion (LVI). Multivariate Cox regression analysis revealed that elevated Snail expression was a significant and an independent prognostic predictor of recurrence-free survival and cancer-specific survival. Patients with positive LVI and high Snail expression showed the worse outcome. Targeting of Snail mRNA expression in UMUC-3 cells with Snail-specific siRNA downregulated the mRNA expression of Snail, Vimentin, MMP2, and MMP9. Furthermore, the cells with siRNA for Snail showed decreased invasion activity in comparison with the cells transfected with a nontargeting siRNA.Conclusion: Snail-induced EMT represents a clinically relevant mechanism of UTUC progression and an attractive target for the treatment of patients with UTUC. Clin Cancer Res; 16(23); 5814-23. (C)2010 AACR.