Nuclear Expression of Hypoxia-inducible Factor-1?? in Clear Cell Renal Cell Carcinoma is Involved in Tumor Progression

Objectives: The most frequent genomic abnormality in clear cell renal cell carcinoma (cc-RCC) is inactivation of Von Hippel-Lindau gene (VHL). pVHL19 is a ligase promoting proteosomal degradation of hypoxia-inducible factor-lalfa (HIF-la); pVHL30 is associated with microtubules. VHL exert its oncogenetic action both directly and through HIF-1α activation. TNM classification is unable to define a correct prognostic evaluation of intracapsular cc-RCC. The nucleo-cytoplasmic trafficking in VHL/HIF-1α pathway could be relevant in understanding the molecular pathogenesis of renal carcinogenesis. This study analyzes VHL/HIF-1α proteins in a large series of intracapsular cc-RCCs, correlating their expression and cellular localization with prognosis. Materials and Methods: Two anti-pVHL (clones Ig32 and Ig33) and 1 anti-HIF-1α were used on tissue microarrays from 136 intracapsular cc-RCCs (mean follow-up: 74 mo). Clone 32 recognizes both pVHLs, whereas clone 33 only pVHL30. Results were matched with clinicopathologic variables and tumor-specific survival (TSS). Results: A strong cytoplasmic positivity was found for all antibodies in the largest part of cases, associated to a strong nuclear localization in the case of HIF-1α. All pVHL-negative cases were associated with high HIF-1α expression. pVHL negativity and HIF-la nuclear positivity significantly correlated with shorter TSS. In multivariate analysis both pVHL negativity and HIF-la nuclear expression were independent predictors of TSS. Conclusions: The localization of the proteins well matches with their role and with the supposed tumor molecular pathways. The correlation with prognosis of VHL/HIF-1α alterations confirms the relevance of their molecular pathway and of the cellular trafficking of their products in the pathogenesis of renal cancer.