Poor prognosis and advanced clinicopathological features of clear cell renal cell carcinoma (ccRCC) are associated with cytoplasmic subcellular localisation of Hypoxia inducible factor-2伪

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• 作者：Nils Kroeger<sup>asup><sup> ; sup><sup>bsup><sup> ; sup><sup>1sup> ; David B. Seligson<sup>csup><sup> ; sup><sup>1sup> ; Sabina Signoretti<sup>dsup> ; Hong Yu<sup>csup> ; Clara E. Magyar<sup>csup> ; Jiaoti Huang<sup>csup> ; Arie S. Belldegrun<sup>asup> ; Allan J. Pantuck<sup>asup><sup> ; sup><sup>apantuck@mednet.ucla.edu" class="auth_mailsup>
• 关键词：Renal cell carcinoma ; CA-IX ; VEGF ; mTOR ; HIF-1 ; HIF-2 ; Tumour suppressor ; Tumour promotor ; Cancer specific survival
• 刊名：European Journal of Cancer
• 出版年：May, 2014
• 年：2014
• 卷：50
• 期：8
• 页码：1531-1540
• 全文大小：2137 K

文摘

ss="h4">Background

Pre-clinical studies have implicated hypoxia inducible factor (HIF)-2伪 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-2伪 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-2伪 would predict clinicopathological features and cancer specific survival (CSS) in ccRCC.

ss="h4">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.

ss="h4">Results

High HIF-2伪 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-2伪 (>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-2伪 C variables remained significant predictors of CSS, while neither HIF-2伪 N variable was retained.

ss="h4">Conclusion

Our investigation supports that HIF-2伪 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-2伪 when located in the cytoplasm.