Cytoplasmic expression of hypoxia inducible factor (HIF)-2α is associated with poor prognosis in patients with clear cell renal cell carcinoma (ccRCC), study findings indicate.
Nuclear expression, on the other hand, does not independently predict survival in these patients, report Allan Pantuck (University of California-Los Angeles, USA) and colleagues in the European Journal of Cancer.
This study not only confirms preclinical study data implicating HIF-2α as an important oncogene in ccRCC, but also extends those findings by demonstrating that the tumour promoter activity may depend on the subcellular localisation of HIF-2α.
“Overall, these findings support further translational approaches that investigate HIF-2α as a target for the treatment of RCC as well as further mechanistic studies that investigate the unique role of HIF-2α in the cytoplasm of ccRCCs”, say the researchers.
Pantuck and team used a tissue microarray to measure HIF-2α expression in tumour samples taken from 308 patients with ccRCC. They observed nuclear expression in 97% of tumours and cytoplasmic expression in 20% of tumours. The majority (97%) of tumours that expressed HIF-2α in the cytoplasm also expressed it in the nucleus.
Furthermore there was no significant difference in the expression of HIF-2α between primary tumours and their corresponding metastases (n=16).
Univariate analyses showed that tumours with high (>32%) nuclear HIF-2α expression were significantly smaller with lower T stages and less advanced Fuhrman grades than those with low expression. High nuclear HIF-2α expression was also associated with longer cancer-specific survival (CSS), but this association was attenuated when TNM stage, Eastern Cooperative Oncology Group performance status and Fuhrman grade were taken into account.
Conversely, any expression of cytoplasmic HIF-2α was associated with more frequent positive lymph nodes, distant metastases and higher Fuhrman grades compared with no expression. Furthermore, CSS was significantly worse among patients with cytoplasmic HIF-2α versus those without it (0.87 vs 2.12 years) and the association remained significant after multivariate analysis.
Of note, patients with low nuclear HIF-2α expression combined with any cytoplasmic HIF-2α expression had the worst outcome of all. They had a 3.7-fold increased risk of death compared with patients who had high nuclear and no cytoplasmic HIF-2α expression.
However, Pantuck and team point out that the relationship between these two markers “needs further external validation before it can be considered as a novel biomarker in ccRCC.”
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