Hypoxia-inducible factor-1α Expression Correlates with Focal Macrophage Infiltration, Angiogenesis and Unfavorable Prognosis in Urothelial Carcinoma

Abstract

Background: Hypoxia inducible factor-1 alpha (HIF-1α) is a critical regulatory protein of cellular response to hypoxia and is closely related to angiogenic process. Aims: To explore the potential role and the prognostic value of HIF-1α in urothelial carcinoma (UC). Methods: Clinicopathological and follow up data on 99 UC cases were reviewed and immunostained for HIF-1α, CD68, VEGF and CD31 antigen. Tumor-associated macrophage (TAM) counts and HIF-1α expression were compared with clinicopathologic characteristics, overall survival (OS) and disease-free survival rates (DFS). Results: High expression of HIF-1α was detected in 55 of 99 (55.6%) tumors. HIF-1α expression was correlated with tumor size, histological grade, tumor invasiveness and recurrence. VEGF and microvessel density (MVD) demonstrated their positive correlation with HIF-1α overexpression, supporting the correlation of HIF-1α upregulation with tumor angiogenesis. Higher TAM infiltration was identified in high expression of HIF-1α cases rather than HIF-1α low expression cases (P=0.002). Kaplan-Meier analysis found that HIF-1α overexpression and high TAM count was only associated with worse DFS (P=0.009, P=0.023) but was not associated with OS (P=0.696, P=0.141). Multivariate analyses indicated only tumor size (P=0.038) to be an independently significant prognostic factors for OS, in addition, HIF-1α expression (P=0.011), as well as histological grade (P=0.038), and MVD (P=0.004), to be independently significant prognostic factors for DFS. Conclusions: Our results indicated that HIF-1α is a key regulator of the angiogenic cascade. We showed that HIF-1α is an independent prognostic factor for disease-free survival.