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; Anil K Sood

doi:10.1038/ncomms6202

Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression

Nat Commun. 2014 Oct 29:5:5202. doi: 10.1038/ncomms6202.

Authors

Rajesha Rupaimoole¹, Sherry Y Wu², Sunila Pradeep², Cristina Ivan³, Chad V Pecot⁴, Kshipra M Gharpure¹, Archana S Nagaraja¹, Guillermo N Armaiz-Pena², Michael McGuire², Behrouz Zand², Heather J Dalton², Justyna Filant², Justin Bottsford Miller², Chunhua Lu², Nouara C Sadaoui¹, Lingegowda S Mangala³, Morgan Taylor², Twan van den Beucken⁵, Elizabeth Koch⁶, Cristian Rodriguez-Aguayo⁷, Li Huang⁸, Menashe Bar-Eli⁸, Bradly G Wouters⁶, Milan Radovich⁹, Mircea Ivan¹⁰, George A Calin⁷, Wei Zhang¹¹, Gabriel Lopez-Berestein⁷, Anil K Sood¹²

Affiliations

¹ 1] Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2] Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
² Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
³ 1] Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2] Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
⁴ Department of Molecular Therapeutics, University of North Carolina Lineberger Comprehensive Cancer Center, 101 Manning Drive, Chapel Hill, North Carolina 27599, USA.
⁵ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
⁶ 1] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 1L7 [2] Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 1L7.
⁷ 1] Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2] Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
⁸ Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
⁹ Department of Surgery, Microbiology and Immunology, Indiana University, 980W Walnut Street, Indianapolis, Indiana 46202, USA.
¹⁰ Department of Medicine, Microbiology and Immunology, Indiana University, 980W Walnut Street, Indianapolis, Indiana 46202, USA.
¹¹ Department of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
¹² 1] Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2] Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [3] Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cell Hypoxia / genetics
Cell Line, Tumor
DEAD-box RNA Helicases / genetics
DEAD-box RNA Helicases / metabolism
Disease Progression*
Down-Regulation / genetics*
Epithelial-Mesenchymal Transition / genetics
Female
Gene Expression Regulation, Neoplastic
Humans
Mice, Nude
MicroRNAs / biosynthesis*
MicroRNAs / genetics
Models, Biological
Neoplasms / drug therapy
Neoplasms / genetics*
Neoplasms / pathology*
Proto-Oncogene Protein c-ets-1 / genetics
Proto-Oncogene Protein c-ets-1 / metabolism
Ribonuclease III / genetics
Ribonuclease III / metabolism
Vascular Endothelial Growth Factor A / antagonists & inhibitors
Vascular Endothelial Growth Factor A / metabolism

Substances

ETS1 protein, human
MicroRNAs
Proto-Oncogene Protein c-ets-1
Vascular Endothelial Growth Factor A
DICER1 protein, human
DROSHA protein, human
Ribonuclease III
DEAD-box RNA Helicases

Abstract

Publication types

MeSH terms

Substances

Grants and funding