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.

Oxidative Stress Increases Endogenous Complement-Dependent Inflammatory and Angiogenic Responses in Retinal Pigment Epithelial Cells Independently of Exogenous Complement Sources

“…We did not detect a change in tgf-β expression (Supplementary Materials, Figure S2K) or IL-10 secretion in H 2 O 2- treated ARPE-19 cells. Therefore, we assumed a proangiogenic function of foxp3 in the cells, as previously reported [22,23]. In line with this, we observed an increase in IL-8 and VEGF-α concentration in the apical supernatant of stressed ARPE-19 cells (Figure 6F,G).…”

“…The signaling pathway is not exactly known so far, but exclusive C5aR1 activation by non-ARPE-19 cell components can be excluded. In regulatory T-cells, the transcription factor FOXP3 promotes the expression of IL-8 [22], and in bladder cancer cells, a knock-down of foxp3 has resulted in the reduced expression of vegf-α [23]. Foxp3 mRNA was expressed in ARPE-19 cells and increased under oxidative stress conditions.…”

“…An antagonizing complement modulation has been described for regulatory T-cells, where C3aR and C5aR1 activation resulted in the activation of the forkhead box P3 (FOXP3) transcription factor [18,21]. The FOXP3 transcription factor acts in multimodal fashion and stimulates the release of anti-inflammatory cytokines and proangiogenic factors [21,22,23].…”

Prognostic significance of CD4-positive regulatory T cells in tumor draining lymph nodes from patients with bladder cancer

“…Based on our observation, the frequency of these FOXP3-expressing cells was much higher in draining lymph nodes from patients with BC compared to other cancers including breast and colon carcinomas [ 7 , 8 ]. The difference may be due to both in situ generation at the tumor site and greater recruitment from the periphery in BC [ 9 , 10 ]. It has been also reported that effector T cells can transiently express FOXP3 after activation.…”

Calycosin Inhibits the Migration and Invasion of Human Breast Cancer Cells by Down-Regulation of Foxp3 Expression

“…Jou et al reported that Foxp3, a member of the forkhead/winged-helix family of transcription regulators, enhances expression of VEGF by binding with hypoxia-inducible factor-1α (HIF-1α) [29]. Thus, we evaluated levels of Foxp3 in calycosin-treated MCF-7 and T47D cells.…”