Investigating the association of cytoplasmic and nuclear HIF-2 expression with cancer specific survival (CSS) in clear cell renal cell carcinoma.

Abstract

387 Background: Studies support the prognostic importance of HIF-2α for ccRCC. Interestingly, a recent study has implicated HIF-2α as part of a protein translational initiation complex, a cytoplasmic function that goes far beyond its role as a nuclear transcription factor. We hypothesized that both the absolute expression as well as the subcellular localization of HIF-2α would predict clinicopathological features and CSS in ccRCC. Methods: A tissue microarray (TMA) study was conducted on 308 ccRCC patients. Survival differences were investigated with the log rank test and associations with CSS with uni- and multivariate Cox regression analyses. Recursive partition tree analysis was used to identify relevant cutoff values. Results: The median follow-up was 2.29 years (IQR 11.82). The mean percentage of positive cells was 22.45±18.00 and 0.12 ± 0.29 for HIF-2α nuclear (N) and cytoplasmic (C), respectively. High HIF-2α N (cutoff>32%) expression was associated with smaller tumor sizes (p = 0.002) and less advanced Fuhrman grades (p = 0.044). To the contrary, tumors with high HIF-2α C (>0%) more often had lymph node (p = 0.004), distant metastases (p = 0.021), and higher Fuhrman grades (p<0.0001). Univariate analyses showed an association of high HIF-2α N (p = 0.035) with better CSS. This was not found when HIF-2α N was used as a continuous variable (p = 0.067). In contrast, HIF-2α C demonstrated an association with CSS when examined as both a continuous (p < 0.0001) and as a dichotomized variable (p < 0.0001). After adjustment for TNM stage, ECOG PS, and Fuhrman grade, both continuous (p < 0.0001) and dichotomized (p < 0.0001) HIF-2α C variables remained significant predictors of CSS, while neither HIF-2α N variable was retained. The ratio of HIF-2α C/N was the strongest predictor of CSS in multivariate analysis (p = 0.001; HR 4.83 [95% CI: 1.99 – 11.76]). Conclusions: Our investigation suggests an important role for HIF-2α as a cytoplasmic protein translational initiation complex in ccRCC. This novel observation warrants further molecular and genetic studies examining biological pathways that are involved in the tumor promotive properties of HIF-2α in the cytoplasm.