The role of ALKBH family in bladder cancer development

研究ALKBH 3在人尿路上皮癌发生发展中的作用和功能。ALKBH 3敲低通过下调NOX-2介导的ROS产生诱导细胞周期停滞在G1期。ALKBH 3敲低通过减少Tweak及其受体Fn 14的表达来减少VEGF的表达。ALKBH 3或Tweak的沉默在体内显著抑制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，而且癌灶内的血管内皮细胞表达Fn 14，其在体内被ALKBH 3和Tweak敲低强烈降低，表明Tweak的ALKBH 3依赖性表达稳定了Fn 14。免疫组化检查显示ALKBH 3、Tweak和Fn 14在尿路上皮癌中高表达，尤其是在高级别浸润性癌中;此外，癌灶内Fn 14阳性血管计数在浸润性表型中增加。ALKBH 3有助于尿路上皮癌的发展。

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.