Foxp3 enhances HIF-1α target gene expression in human bladder cancer through decreasing its ubiquitin-proteasomal degradation
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Yeong-Chin Jou1,*, Yuh-Shyan Tsai2,*, Chang-Te Lin1, Chun-Liang Tung3, Cheng-Huang Shen1, Hsin-Tzu Tsai2, Wen-Horng Yang2, Hung-I Chang2, Syue-Yi Chen4, Tzong-Shin Tzai5,6
1Department of Urology, Chia-Yi Christian Hospital, Chia-Yi, Taiwan
2Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
3Department of Pathology, Chia-Yi Christian Hospital, Chia-Yi, Taiwan
4Department of Medical Researh, Chia-Yi Christian Hospital, Chia-Yi, Taiwan
5Department of Urology, School of Medicine, China Medical University, Taichung, Taiwan
6Department of Urology, Tainan Municipal An-Nan Hospital, China Medical University, Tainan, Taiwan
*These authors have contributed equally to this work
Yuh-Shyan Tsai, email: firstname.lastname@example.org
Tzong-Shin Tzai, email: D71569@mail.tmanh.org.tw
Keywords: bladder neoplasms, Foxp3, immunohistochemistry, prognosis, glycolysis
Received: December 14, 2015 Accepted: August 08, 2016 Published: August 19, 2016
Hypoxia-inducible factor-1α (HIF-1α) can control a transcriptional factor forkhead box P3 (Foxp3) protein expression in T lymphocyte differentiation through proteasome-mediated degradation. In this study, we unveil a reverse regulatory mechanism contributing to bladder cancer progression; Foxp3 expression attenuates HIF-1α degradation. We first demonstrated that Foxp3 expression positively correlates with the metastatic potential in T24 cells and can increase the expression of HIF-1α-target genes, such as vascular endothelial growth factor (VEGF) and glucose transporter (GLUT). Foxp3 protein can bind with HIF-1α, particularly under hypoxia. In vivo ubiquination assay demonstrated that Foxp3 can decrease HIF-1α degradation in a dose-dependent manner. 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. Thirty-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 positively associated with GLUT-4,-9, and VEGF-A, B-, D expression. This reverse post-translational regulation of HIF-1α protein by Foxp3 provides a new potential target for developing new therapeutic strategy for bladder cancer.
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