Angiogenesis Driven by the CEBPD–hsa-miR-429–VEGFA Signaling Axis Promotes Urothelial Carcinoma Progression

Background and Purpose: This research aimed to excavate the alternative mechanism of CEBPD on tumor growth and explore the biological significance of the CEBPD/hsa-miR-429/VEGFA axis on angiogenesis in urothelial carcinoma (UC). Methods: Quantitative RT-PCR, immunoblotting assay and tube formation examined the effect of hsa-miR-429 mimic or/and inhibitor on VEGFA expression and angiogenesis in CEBPD-overexpressing UC-derived cells. The association between CEBPD, hsa-miR-429, VEGFA and microvascular density (MVD) and clinical outcome were evaluated in 296 patients with UBUC and 340 patients with UTUC, respectively. Results: The increase in the transcript and protein of VEGFA as well as HUVECs tube formation was diminished upon the treatment of hsa-miR-429 mimic in CEBPD-overexpressing BFTC909 and TCCSUP. Nevertheless, the inhibited regulation of hsa-miR-429 mimic on the expression of VEGFA and ability of HUVECs tube formation was rescued by the combined incubation with hsa-miR-429 inhibitor in these two UC-derived cell lines. Furthermore, the clinical correlations showed that the higher level of VEGFA or MVD has a positive correlation with the expression of CEBPD and a negative relation to hsa-miR-429 and leads to tumor aggressiveness with worse disease-specific, metastasis-free survival in UBUC and UTUC cohorts. Conclusions: We decipher the oncogenic mechanism of CEBPD on angiogenesis through the hsa-miR-429 inhibition to stabilize the expression of VEGFA in UC. The novel research unveiled the modulation of the CEBPD/hsa-miR-429/VEGFA axis on the progression of UC and could be accessible to theranostic biomarkers.