期刊
NATURE COMMUNICATIONS
卷 5, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms6202
关键词
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资金
- National Institutes of Health [CA016672, CA109298, CA177909, UH2TR000943, P50 CA083639, P50 CA098258, U54 CA151668, U24CA143835]
- Cancer Prevention and Research Institute of Texas [RP110595, RP120214, RP101502, RP101489]
- Ovarian Cancer Research Fund, Inc.
- Department of Defense [OC073399, OC120547]
- Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer
- RGK Foundation
- Gilder Foundation
- Judi A Rees ovarian cancer research fund
- Mr and Mrs Daniel P. Gordon, H. A. and Mary K. Chapman charitable foundation
- Golfers Against Cancer
- Blanton-Davis Ovarian Cancer Research Program
- Betty Anne Asche Murray Distinguished Professorship
- Russell and Diana Hawkins Family Foundation
- National Cancer Institute [CA009666]
- Conquer Cancer Foundation ASCO
- DoCM Advanced Scholar Program
- Foundation for Women's Cancer
- NCI-DHHS-NIH [T32 CA101642]
- National Institute of Health [CA155332]
- Terry Fox New Frontiers Research Program [PPG-1036]
- Ontario Institute for Cancer Research
- Terry Fox Research Institute Stem Cell Program
- Canadian Institute for Health Research (CIHR) [201592]
- Canadian Breast Cancer Foundation (CBCF)
Cancer-related deregulation of miRNA biogenesis has been suggested, but the underlying mechanisms remain elusive. Here we report a previously unrecognized effect of hypoxia in the downregulation of Drosha and Dicer in cancer cells that leads to dysregulation of miRNA biogenesis and increased tumour progression. We show that hypoxia-mediated downregulation of Drosha is dependent on ETS1/ELK1 transcription factors. Moreover, mature miRNA array and deep sequencing studies reveal altered miRNA maturation in cells under hypoxic conditions. At a functional level, this phenomenon results in increased cancer progression in vitro and in vivo, and data from patient samples are suggestive of miRNA biogenesis downregulation in hypoxic tumours. Rescue of Drosha by siRNAs targeting ETS1/ELK1 in vivo results in significant tumour regression. These findings provide a new link in the mechanistic understanding of global miRNA downregulation in the tumour microenvironment.
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