Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression. Nat Commun 2014 Oct 29;5:5202
Date
10/30/2014Pubmed ID
25351346Pubmed Central ID
PMC4215647DOI
10.1038/ncomms6202Scopus ID
2-s2.0-84923276259 (requires institutional sign-in at Scopus site) 158 CitationsAbstract
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.
Author List
Rupaimoole R, Wu SY, Pradeep S, Ivan C, Pecot CV, Gharpure KM, Nagaraja AS, Armaiz-Pena GN, McGuire M, Zand B, Dalton HJ, Filant J, Miller JB, Lu C, Sadaoui NC, Mangala LS, Taylor M, van den Beucken T, Koch E, Rodriguez-Aguayo C, Huang L, Bar-Eli M, Wouters BG, Radovich M, Ivan M, Calin GA, Zhang W, Lopez-Berestein G, Sood AKAuthor
Sunila Pradeep PhD Associate Professor in the Obstetrics and Gynecology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCell Hypoxia
Cell Line, Tumor
DEAD-box RNA Helicases
Disease Progression
Down-Regulation
Epithelial-Mesenchymal Transition
Female
Gene Expression Regulation, Neoplastic
Humans
Mice, Nude
MicroRNAs
Models, Biological
Neoplasms
Proto-Oncogene Protein c-ets-1
Ribonuclease III
Vascular Endothelial Growth Factor A
