Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression

Rajesha Rupaimoole, Sherry Y. Wu, Sunila Pradeep, Cristina Ivan, Chad V. Pecot, Kshipra M. Gharpure, Archana S. Nagaraja, Guillermo N. Armaiz-Pena, Michael McGuire, Behrouz Zand, Heather J. Dalton, Justyna Filant, Justin Bottsford Miller, Chunhua Lu, Nouara C. Sadaoui, Lingegowda S. Mangala, Morgan Taylor, Twan van den Beucken, Elizabeth Koch, Cristian Rodriguez-Aguayo, Li Huang, Menashe Bar-Eli, Bradly G. Wouters, Milan Radovich, Mircea Ivan, George A. Calin, Wei Zhang, Gabriel Lopez-Berestein and Anil K. Sood ()
Additional contact information
Rajesha Rupaimoole: The University of Texas MD Anderson Cancer Center
Sherry Y. Wu: The University of Texas MD Anderson Cancer Center
Sunila Pradeep: The University of Texas MD Anderson Cancer Center
Cristina Ivan: The University of Texas MD Anderson Cancer Center
Chad V. Pecot: University of North Carolina Lineberger Comprehensive Cancer Center
Kshipra M. Gharpure: The University of Texas MD Anderson Cancer Center
Archana S. Nagaraja: The University of Texas MD Anderson Cancer Center
Guillermo N. Armaiz-Pena: The University of Texas MD Anderson Cancer Center
Michael McGuire: The University of Texas MD Anderson Cancer Center
Behrouz Zand: The University of Texas MD Anderson Cancer Center
Heather J. Dalton: The University of Texas MD Anderson Cancer Center
Justyna Filant: The University of Texas MD Anderson Cancer Center
Justin Bottsford Miller: The University of Texas MD Anderson Cancer Center
Chunhua Lu: The University of Texas MD Anderson Cancer Center
Nouara C. Sadaoui: The University of Texas MD Anderson Cancer Center
Lingegowda S. Mangala: The University of Texas MD Anderson Cancer Center
Morgan Taylor: The University of Texas MD Anderson Cancer Center
Twan van den Beucken: University of Toronto, Toronto
Elizabeth Koch: University of Toronto, Toronto
Cristian Rodriguez-Aguayo: Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center
Li Huang: The University of Texas MD Anderson Cancer Center
Menashe Bar-Eli: The University of Texas MD Anderson Cancer Center
Bradly G. Wouters: University of Toronto, Toronto
Milan Radovich: Microbiology and Immunology, Indiana University
Mircea Ivan: Microbiology and Immunology, Indiana University
George A. Calin: Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center
Wei Zhang: The University of Texas MD Anderson Cancer Center
Gabriel Lopez-Berestein: Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center
Anil K. Sood: The University of Texas MD Anderson Cancer Center

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: Abstract 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.

Date: 2014
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6202

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DOI: 10.1038/ncomms6202

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