Abstract
Background
Pre-clinical studies have implicated hypoxia inducible factor (HIF)-2α as an important
oncogene for clear cell renal cell carcinoma (ccRCC). Generally considered to act
as a nuclear transcription factor, a recent study has also implicated HIF-2α as a
protein translational initiation complex function within the cytoplasm (Uniacke et
al., 2012). We hypothesised that both the absolute expression as well as the sub-cellular
localisation of HIF-2α would predict clinicopathological features and cancer specific
survival (CSS) in ccRCC.
Methods
A tissue microarray (TMA) study was conducted on three hundred and eight 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
High HIF-2α nuclear (N) (cutoff >32%) expression was associated with smaller tumour
sizes (p = 0.002) and lower Fuhrman grades (p = 0.044), whereas tumours with high cytoplasmic (C) HIF-2α (>0%) more often had positive
lymph nodes (p = 0.004), distant metastases (p = 0.021) and higher Fuhrman grades (p < 0.0001). After adjustment for TNM stage, Eastern Cooperative Oncology Group performance
status (ECOG PS), and Fuhrman grade, both continuous (p < 0.0001) and dichotomised (p < 0.0001) HIF-2α C variables remained significant predictors of CSS, while neither HIF-2α
N variable was retained.
Conclusion
Our investigation supports that HIF-2α may have a unique tumour promoter role in the
cytoplasm. This preliminary finding justifies further experimental and mechanistic
studies that examine the biological functions of HIF-2α when located in the cytoplasm.
Keywords
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Article info
Publication history
Published online: February 24, 2014
Identification
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© 2014 Elsevier Ltd. Published by Elsevier Inc. All rights reserved.
