title: Foxp3 enhances HIF-1α target gene expression in human bladder cancer through decreasing its ubiquitin-proteasomal degradation.
abstract: 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.
authors.affiliation: Department of Urology, Chia-Yi Christian Hospital, Chia-Yi, Taiwan.
authors.forename: Yeong-Chin
authors.initials: YC
authors.lastname: Jou
authors.affiliation: Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yuh-Shyan
authors.initials: YS
authors.lastname: Tsai
authors.affiliation: Department of Urology, Chia-Yi Christian Hospital, Chia-Yi, Taiwan.
authors.forename: Chang-Te
authors.initials: CT
authors.lastname: Lin
authors.affiliation: Department of Pathology, Chia-Yi Christian Hospital, Chia-Yi, Taiwan.
authors.forename: Chun-Liang
authors.initials: CL
authors.lastname: Tung
authors.affiliation: Department of Urology, Chia-Yi Christian Hospital, Chia-Yi, Taiwan.
authors.forename: Cheng-Huang
authors.initials: CH
authors.lastname: Shen
authors.affiliation: Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Hsin-Tzu
authors.initials: HT
authors.lastname: Tsai
authors.affiliation: Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Wen-Horng
authors.initials: WH
authors.lastname: Yang
authors.affiliation: Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Hung-I
authors.initials: HI
authors.lastname: Chang
authors.affiliation: Department of Medical Researh, Chia-Yi Christian Hospital, Chia-Yi, Taiwan.
authors.forename: Syue-Yi
authors.initials: SY
authors.lastname: Chen
authors.affiliation: Department of Urology, School of Medicine, China Medical University, Taichung, Taiwan.|Department of Urology, Tainan Municipal An-Nan Hospital, China Medical University, Tainan, Taiwan.
authors.forename: Tzong-Shin
authors.initials: TS
authors.lastname: Tzai
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics; D016019:Survival Analysis; D054875:Ubiquitination; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality
chemical_list: D014408:Biomarkers, Tumor; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D046988:Proteasome Endopeptidase Complex
keywords: Foxp3; bladder neoplasms; glycolysis; immunohistochemistry; prognosis