The role of ALKBH family in bladder cancer development

检测ALKBH3在人尿路上皮癌发生发展中的作用和功能。ALKBH3基因敲除通过下调NOX-2介导的ROS生成，诱导细胞周期停滞于G1期。ALKBH3基因敲除通过降低TWEEP及其受体Fn14的表达来降低血管内皮生长因子的表达。沉默ALKBH3或TWEEP可显著抑制体内尿路上皮癌的侵袭和血管生成。有趣的是，不仅尿路上皮癌细胞表达Fn14，癌灶内的血管内皮细胞也表达Fn14，在体内被ALKBH3和TWEK基因敲除后Fn14表达显著减少，表明ALKBH3依赖的TWEK表达稳定了Fn14。免疫组织化学检测显示ALKBH3、TWEEP和Fn14在尿路上皮癌中高表达，尤其是在高级别浸润性癌中，而且癌灶内Fn14阳性血管计数在浸润性表型中增加。ALKBH3与尿路上皮癌的发生有关。

The role and function of ALKBH3 in human urothelial carcinoma development were examined. ALKBH3 knockdown induced cell cycle arrest at the G1 phase through downregulation of NOX-2-mediated generation of ROS. ALKBH3 knockdown reduced VEGF expression by reducing expression of Tweak and its receptor, Fn14. Silencing of ALKBH3 or Tweak significantly suppressed invasion and angiogenesis of urothelial carcinoma in vivo . Interestingly, not only urothelial carcinoma cells but also vascular endothelial cells within cancer foci expressed Fn14, which was strongly reduced by ALKBH3 and Tweak knockdown in vivo, suggesting that ALKBH3-dependent expression of Tweak stabilizes Fn14. Immunohistochemical examination showed high expression of ALKBH3, Tweak, and Fn14 in urothelial carcinoma, especially in high-grade, invasive carcinomas; moreover, Fn14-positive vessel counts within cancer foci were increased in invasive phenotypes. ALKBH3 contributes to development of urothelial carcinomas.