Fopx3在膀胱癌會結合且調節HIF-1a-VEGF訊息
蔡育賢1、周詠欽2、林昌德2、沈正煌2、陳學毅3、蔡欣孜1、楊文宏1、蔡宗欣1
1國立成功大學醫學院附設醫院泌尿部；2嘉義基督教醫院外科部泌尿科；3醫學研究部
Foxp3 interacts with and regulates HIF-1a-VEGF signaling in human bladder cancer
Yuh-Shyan Tsai1, Yeong-Chin Jou2, Chang-Te Lin2, Cheng-Huang Shen2, Syue-Yi Chen3, Hsin-Tzu Tsai1, Wen-Horng Yang1, and Tzong-Shin Tzai1
Department of Urology1, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
Department of Urology2, and Medical Researh3, Chia-Yi Christian Hospital, Chia-Yi, Taiwan
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 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. Knocking-down 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 (p= 0.032), 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
Conclusions: 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.