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hsa-miR-210 Is Induced by Hypoxia and Is an Independent Prognostic Factor in Breast Cancer

Authors' Affiliations: ¹ Genomics Group, Wellcome Trust Centre for Human Genetics, The Henry Wellcome Building for Genomic Medicine, University of Oxford, ² Oxygen Sensing Group, The Henry Wellcome Building for Molecular Physiology, University of Oxford, ³ Cancer Research UK Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom, and ⁴ Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Belgium

Requests for reprints: Jiannis Ragoussis, Genomics Group, Wellcome Trust Centre for Human Genetics, The Henry Wellcome Building for Genomic Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom. E-mail: ioannis.ragoussis{at}well.ox.ac.uk.

Purpose: MicroRNA (miRNA) expression alterations have been described in cancer. Many cancers are characterized by areas of hypoxia, enhanced hypoxia-inducible factor (HIF) levels, and increased expression of hypoxically regulated genes, all of which correlate with patient outcome. We examined hypoxia-induced miRNA expression changes to identify markers of survival in breast cancer.

Experimental Design: We used microarrays to analyze miRNA expression changes induced by hypoxia in MCF7 breast cancer cell lines and validated results by quantitative-PCR (Q-PCR). Small interfering RNA against HIF-1 and HIF-2, and RCC4 cells transfected with the von Hippel-Lindau (VHL) protein were used to investigate HIF dependency of miRNA expression. miRNA Q-PCR assays were done on 219 early breast cancer samples with long-term follow-up. Correlation of expression with clinical variables was done using Pearson and Spearman's rank tests, univariate, and Cox multivariate analysis.

Results: hsa-miR-210 induction was the most significant change under hypoxia by microarray analysis (3.4-fold, P < 0.001). hsa-miR-210 expression changes were validated by Q-PCR and detected in other cancer cell lines. Using small interfering RNAs and RCC4 cells transfected with VHL, we showed that the regulation by hypoxia of hsa-miR-210 was mediated by the HIF-1/VHL transcriptional system but not HIF-2. hsa-miR-210 expression levels in breast cancer samples correlated directly with a hypoxia score based on the expression of 99 genes. hsa-miR-210 expression levels showed an inverse correlation with disease-free and overall survival, significant in both univariate and multivariate analyses.

Conclusions: We show that hsa-miR-210 overexpression is induced by hypoxia in a HIF-1– and VHL-dependent fashion and its expression levels in breast cancer samples are an independent prognostic factor.

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