Department of Urology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Clin Cancer Res. 2010 Dec 1;16(23):5814-23. doi: 10.1158/1078-0432.CCR-10-0230. Epub 2010 Oct 14.
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.
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.
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.
Snail-induced EMT represents a clinically relevant mechanism of UTUC progression and an attractive target for the treatment of patients with UTUC.
目前仅有少数分子标志物可用于预测上尿路尿路上皮癌（UTUC）的预后。Snail 可促进上皮间质转化（EMT），已在癌症进展中得到证实，但在 UTUC 中尚不清楚。因此，我们研究了 Snail 在 UTUC 中的表达及其生物学意义。
为了阐明 Snail 在 UTUC 中的生物学意义，我们检测了 150 例 UTUC 患者组织中 Snail 的免疫组化表达，并分析了其临床意义。采用针对尿路上皮癌细胞系的 Snail 特异性小干扰 RNA（siRNA）和 Matrigel 侵袭试验，评估了 Snail 在 EMT 和侵袭中的生物学效应。
在上尿路尿路上皮癌中，Snail 的核染色很弱。相比之下，侵袭性 UTUC 中有许多细胞核中 Snail 染色较强。Snail 表达在肿瘤分期高、分级高和存在脉管侵犯（LVI）的患者中显著升高。多因素 Cox 回归分析显示，Snail 表达升高是无复发生存和癌症特异性生存的显著独立预后预测因子。LVI 阳性和 Snail 高表达的患者预后更差。用 Snail 特异性 siRNA 靶向 UMUC-3 细胞中的 Snail mRNA 表达，下调了 Snail、波形蛋白、MMP2 和 MMP9 的 mRNA 表达。此外，与转染非靶向 siRNA 的细胞相比，用 Snail siRNA 转染的细胞侵袭活性降低。
Snail 诱导的 EMT 代表了 UTUC 进展的一种具有临床意义的机制，是治疗 UTUC 患者的一个有吸引力的靶点。
Zotero 插件