FOXP3 interacts with and regulates HIF-1α-VEGF signaling in human bladder cancer

Yuh-Shyan Tsai, Yeong-Chin Jou, Chang-Te Lin, Cheng-Huang Shen, Syue-Yi Chen, Hsin-Tzu Tsai, Wen-Horng Yang, Tzong-Shin Tzai
2016 Urological Science  
Purpose: To investigate the prognostic role and molecular mechanism of Foxp3 expression in human bladder cancer. Materials and Methods: Using quantitative RT-PCR and western blotting analysis, T24 parental and metastatic sublines were investigated for Foxp3, glucose transporter ( GLUT), and VEGF expression. The interaction between Foxp3 and HIF-1a were explored using immunoprecipitation, and confocal microscopic studies. Foxp3 expression was examined for the prognostic values in bladder
more » ... in bladder urothelial carcinoma using Foxp3 and CD8 immunostaining. Using data mining, the association between Foxp3, VEGF, and GLUT member expression were explored. Results: Foxp3 expression is associated with the metastatic potential among three human bladder cancer T24 sublines, as well as higher expression of glucose transporter (GLUT) members and vascular endothelial growth factor (VEGF) expression and more aerobic glycolysis. Via immunoprecipitation, and confocal microscopic studies, Foxp3 protein can bind with and maintain HIF-1a expression post-translationally. Knockingdown of Foxp3 expression blocks in vivo tumor growth in mice and prolongs mice's survival, which is associated with von Willebrand factor expression. Forty-three of 145 (22.8 %) bladder tumors exhibit Foxp3 expression. Foxp3 expression is an independent predictor for disease progression in superficial bladder cancer patients (p¼0.032), associated with less number of intratumoral CD8 + lymphocyte. The metaanalysis from 2 published datasets showed Foxp3 expression is associated with GLUT-4,-9, and VEGF-A, B-, D expression Conclusion: Foxp3 expression in bladder tumor cells can bind with and regulate HIF-1a signaling post-translationally, contributing to be an independent prognostic marker for progression in bladder cancer.
doi:10.1016/j.urols.2016.05.166 fatcat:aapp6xl5gfaajag3x64kymqgsy