Bladder Cancer Exosomes Contain EDIL-3/Del1 and Facilitate Cancer Progression
Bladder Cancer Exosomes Contain EDIL-3/Del1 and Facilitate Cancer Progression
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DOI：
10.1016/j.juro.2014.02.035
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发表时间：
2014-08-01
影响因子：
6.6
通讯作者：
Lee, Yi-Fen
中科院分区：
文献类型：
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作者：
Beckham, Carla J.;Olsen, Jayme;Lee, Yi-Fen
目的：高级别膀胱癌是一种侵袭性极强的恶性肿瘤，具有较高的发病率和死亡率。了解外切体可能如何影响膀胱癌的进展可以揭示新的治疗靶点。材料和方法：在标准检测中评估从人膀胱癌细胞系和高级别膀胱癌患者的尿中提取的外切体促进肿瘤进展的能力。从高级别膀胱癌细胞系TCC-SUP和非恶性尿路上皮细胞系SV-Huc中提纯的外切体进行了质谱分析。对EDIL-3进行了鉴定和筛选，以供进一步分析。用Western印迹法检测高级别膀胱癌患者尿液外切体中EDIL-3的水平。利用shRNA基因敲除和重组EDIL-3研究EDIL-3的功能。结果：从高级别膀胱癌细胞和高级别膀胱癌患者尿液中分离的外切体促进了膀胱癌细胞和血管内皮细胞的血管生成和迁移。我们沉默了EDIL-3的表达，发现shEDIL-3外切体不促进血管生成，也不促进尿路上皮细胞和内皮细胞的迁移。此外，从高级别膀胱癌患者尿液中提纯的外切体所含的EDIL-3水平显著高于健康对照组尿液中的外切体。Edil-3激活表皮生长因子受体信号转导，阻断Edil-3诱导的膀胱细胞迁移。结论：膀胱癌患者尿液中含有Edil-3等生物活性分子。识别这些成分及其相关的致癌途径可能会导致新的治疗靶点和治疗策略。
Purpose: High grade bladder cancer is an extremely aggressive malignancy associated with high rates of morbidity and mortality. Understanding how exosomesmay affect bladder cancer progression could reveal novel therapeutic targets.Materials and Methods: Exosomes derived from human bladder cancer cell lines and the urine of patients with high grade bladder cancer were assessed for the ability to promote cancer progression in standard assays. Exosomes purified from the high grade bladder cancer cell line TCC-SUP and the nonmalignant urothelial cell line SV-HUC were submitted for mass spectrometry analysis. EDIL-3 was identified and selected for further analysis. Western blot was done to determine EDIL-3 levels in urinary exosomes from patients with high grade bladder cancer. shRNA gene knockdown and recombinant EDIL-3 were applied to study EDIL-3 function.Results: Exosomes isolated from high grade bladder cancer cells and the urine of patients with high grade bladder cancer promoted angiogenesis and migration of bladder cancer cells and endothelial cells. We silenced EDIL-3 expression and found that shEDIL-3 exosomes did not facilitate angiogenesis, and urothelial and endothelial cell migration. Moreover, exosomes purified from the urine of patients with high grade bladder cancer contained significantly higher EDIL-3 levels than exosomes from the urine of healthy controls. EDIL-3 activated epidermal growth factor receptor signaling while blockade of epidermal growth factor receptor signaling abrogated this EDIL-3 induced bladder cell migration.Conclusions: Exosomes derived from the urine of patients with bladder cancer contains bioactive molecules such as EDIL-3. Identifying these components and their associated oncogenic pathways could lead to novel therapeutic targets and treatment strategies.