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The Expression of Hypoxia-Inducible Factor 1 Is a Favorable Independent Prognostic Factor in Renal Cell Carcinoma

Departments of ¹ Surgical and Perioperative Sciences, Urology and Andrology, ² Medical Biosciences, Pathology, ³ Medical Biosciences, Clinical Chemistry, and ⁴ Radiation Sciences, Oncology, Umeå University, Umeå, Sweden

Requests for reprints: Börje Ljungberg, Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, S-901 85 Umeå, Sweden. Phone: 90-785-1330; Fax: 90-125396; E-mail: borje.ljungberg{at}urologi.umu.se.

Purpose: Renal cell carcinoma (RCC) is the most common malignancy of the kidney composed of specific tumor types. The sporadic conventional RCCs are, in contrast to the other RCC types, characterized by a high rate of von Hippel-Lindau (VHL) mutations and hypermethylation. The majority of these tumors lack functional VHL protein (pVHL) that leads to increased hypoxia-inducible factor 1 (HIF-1) expression. The pVHL is the physiologic regulator of the activity of HIF-1 by targeting it to the proteasome for degradation under normoxia. Both pVHL and HIF-1 target other genes that are important for cancer survival and proliferation. Expression of HIF-1 has been linked to poor prognosis in different malignancies, although few studies have been done on the relation between HIF-1 and clinical variables in RCC.

Experimental Design: HIF-1 protein expression was analyzed in tumor tissue from 92 patients with RCC. HIF-1 was quantified by Western blot relative to a positive control.

Results: The HIF-1 protein was expressed as two bands which strongly correlated (r = 0.906, P < 0.001); therefore, they were added and the sum evaluated against clinicopathologic variables. There was no association between HIF-1 and gender, stage, grade, tumor size, or vein invasion. Conventional RCCs had significantly higher HIF-1 expression compared with papillary and chromophobe RCCs and kidney cortex. In conventional RCC, HIF-1 was an independent prognostic factor.

Conclusion: HIF-1 levels varied significantly between the different RCC types. In conventional RCC, HIF-1 was an independent prognostic factor. These data indicate that HIF-1 is involved in tumorogenesis and progression of RCC. Evaluation of other HIF target gene products and correlation to angiogenesis seems warranted.

Key Words: hypoxia-inducible factor • HIF-1 • renal cell carcinoma • prognosis • Western blot

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