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Hypoxia-inducible factor-1 expression correlates with focal macrophage infiltration, angiogenesis and unfavourable prognosis in urothelial carcinoma

¹ Department of Pathology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
² Department of Pathology, Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung, Taiwan
³ Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
⁴ Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

Correspondence to:
C-Y Chai, Department of Pathology, Kaohsiung Medical University Chung-Ho Memorial Hospital, No. 100, Tzyou 1st Road, Kaohsiung City 807, Taiwan; cychai{at}kmu.edu.tw

Background: Hypoxia inducible factor (HIF)-1 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-1 in urothelial carcinoma (UC).

Methods: Clinicopathological and follow-up data on 99 UC cases were reviewed and immunostained for HIF-1, CD68, vascular endothelial growth factor (VEGF) and CD34 antigen. Tumour-associated macrophage (TAM) counts and HIF-1 expression were compared with clinicopathologic characteristics, overall survival (OS) and disease-free survival rates (DFS).

Results: High expression of HIF-1 was detected in 55 of 99 (55.6%) tumours. HIF-1 expression was correlated with tumour size, histological grade, tumour invasiveness and recurrence. VEGF and microvessel density (MVD) demonstrated their positive correlation with HIF-1 overexpression, supporting the correlation of HIF-1 up-regulation with tumour angiogenesis. Higher TAM infiltration was identified in high expression of HIF-1 cases rather than HIF-1 low expression cases (p = 0.002). Kaplan–Meier analysis found that HIF-1 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 tumour size (p = 0.038) to be an independently significant prognostic factor for OS, in addition, HIF-1 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 indicate that HIF-1 is a key regulator of the angiogenic cascade. We show that HIF-1 is an independent prognostic factor for disease-free survival.