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Background: Upper tract urothelial carcinoma (UTUC) is a rare tumor with extraordinarily different features between Eastern and Western countries. Vascular endothelial growth factor‐A (VEGFA) was originally identified as a secreted signaling protein and regulator of vascular development and cancer progression. In this study, we aimed to elucidate the molecular mechanisms underlying the regulation of VEGFA by microRNA in UTUC. Methods: VEGFA expression was evaluated by immunohistochemistry in 140 human UTUC tissue samples. Next, we assessed the regulatory relationship between VEGFA and miR‐299‐3p by real‐time PCR, western blotting, ELISA and dual‐luciferase reporter assays using two UTUC cell lines. The role of miR‐299‐3p/VEGFA in cell proliferation, motility, invasion, and tube formation was analyzed in vitro. Results: High VEGFA expression was significantly associated with tumor stage, grade, distant metastasis and cancer‐related death and correlated with poor progression‐free and cancer‐specific survival. VEGFA knockdown repressed proliferation, migration, invasion and angiogenesis in UTUC cell lines. miR‐299‐3p significantly reduced VEGFA protein expression and miR‐299‐3p overexpression inhibited VEGFA mRNA and protein expression by directly targeting its 3′‐UTR. Functional studies indicated that VEGFA overexpression reversed the miR‐299‐3p‐mediated suppression of tumor cell proliferation, migration, invasion and angiogenesis. In addition, miR‐299‐3p/VEGFA suppressed cellular functions in UTUC by modulating the expression of P18 and cyclin E2. Conclusions: Our findings suggest that miR‐299‐3p possibly suppresses UTUC cell proliferation, motility, invasion and angiogenesis via VEGFA. VEGFA may act as a prognostic predictor, and both VEGFA and miR‐299‐3p could be potential therapeutic targets for UTUC. [ABSTRACT FROM AUTHOR]

Upper tract urothelial carcinoma (UTUC) is a rare tumor with an incidence that varies greatly between Eastern and Western countries. Transaldolase 1 (TALDO1) is a rate‐limiting enzyme of the pentose phosphate pathway. In humans, aberrant TALDO1 activity has been implicated in various autoimmune diseases and malignancies; however, the function of TALDO1 in UTUC has not been previously investigated. Here we evaluated the clinical significance of TALDO1 expression in 115 paraffin‐embedded tumor samples from patients with UTUC using immunohistochemistry. Our results demonstrated that there was an association between high TALDO1 expression and advanced stage (P = 0.011), tumor size (P = 0.005), tumor location (P = 0.047), distant metastases (P = 0.023), local recurrence (P = 0.002), and cancer death (P = 0.003). Using univariate and multivariate analyses, we found that chemotherapy was an independent factor for bladder recurrence‐free survival. Late stage (III/IV) and high TALDO1 expression were independent prognostic factors for progression‐free and cancer‐specific survival. In summary, increased TALDO1 expression in UTUC was significantly correlated with late stage, tumor size, tumor location, distant metastases, local recurrence, and cancer death. Therefore, high TALDO1 expression could be a predictor of poor survival in patients with UTUC. Further studies are necessary to investigate the role of TALDO1 in UTUC development. [ABSTRACT FROM AUTHOR]