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Expression of Hypoxia-Inducible Factor-1 Protein Predicts Survival in Patients with Transitional Cell Carcinoma of the Upper Urinary Tract

Authors' Affiliations: Departments of ¹ Pathology, ² Laboratory Medicine, ³ Central Research Laboratory, and ⁴ Surgery National Defense Medical College, Tokorozawa, Japan

Requests for reprints: Kuniaki Nakanishi, Department of Pathology, National Defense Medical College, Tokorozawa 359-8513, Japan. Phone: 81-4-2995-1505; Fax: 81-4-2991-5192; E-mail: nknsknak{at}res.ndmc.ac.jp.

Hypoxia-inducible factor-1 (HIF-1), identified as one of the transcription factors, has been found to play an essential role in oxygen homeostasis. HIF-1 is a heterodimer composed of HIF-1 and HIF-1ß. Increased levels of HIF-1 have been reported during the carcinogenesis and progress of several tumors. We investigated the prognostic importance of HIF-1 expression in transitional cell carcinoma of the upper urinary tract. In 127 cases of transitional cell carcinoma of the upper urinary tract, we examined its expression (using immunohistochemistry and in situ hybridization), and also its relation to the expression of p53 oncoprotein, as well as to proliferating cell nuclear antigen (PCNA) immunoreactivity, microvessel density, clinicopathologic parameters, and clinical outcome. A positive expression of HIF-1 protein was recognized in 55.1% of samples, the expression being apparent within the nucleus in tumor cells. HIF-1 protein expression correlated with grade, growth pattern, p53 oncoprotein expression, and PCNA index, but not with stage. Furthermore, a significant correlation was found between HIF-1 protein expression and both overall and disease-free survival rates in the univariate and multivariate analyses (in all tumors and in invasive tumors). A positive expression of HIF-1 mRNA was recognized in 69.6% of 125 samples which were available, the expression being apparent within the cytoplasm in tumor cells. The positive expression of HIF-1 mRNA by in situ hybridization correlated significantly with HIF-1 protein expression by immunohistochemistry. HIF-1 mRNA expression only correlated with pattern of growth (P = 0.0078). In conclusion, the detection of HIF-1 protein would seem to be of value in informing the prognosis of transitional cell carcinoma of the upper urinary tract.

Key Words: transitional cell carcinoma • upper urinary tract • HIF-1 • prognosis

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