Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression

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...

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Vydané v:	Nature communications Ročník 5; číslo 1; s. 5202
Hlavní autori:	Rupaimoole, Rajesha, Wu, Sherry Y., Pradeep, Sunila, Ivan, Cristina, Pecot, Chad V., Gharpure, Kshipra M., Nagaraja, Archana S., Armaiz-Pena, Guillermo N., McGuire, Michael, Zand, Behrouz, Dalton, Heather J., Filant, Justyna, Miller, Justin Bottsford, Lu, Chunhua, Sadaoui, Nouara C., Mangala, Lingegowda S., Taylor, Morgan, van den Beucken, Twan, Koch, Elizabeth, Rodriguez-Aguayo, Cristian, Huang, Li, Bar-Eli, Menashe, Wouters, Bradly G., Radovich, Milan, Ivan, Mircea, Calin, George A., Zhang, Wei, Lopez-Berestein, Gabriel, Sood, Anil K.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 29.10.2014 Nature Publishing Group
Predmet:	13/106 13/109 13/31 13/89 14/1 14/5 14/63 38/15 38/22 38/39 59 631/337 631/67 64/60 82/51 Animals Biosynthesis Cancer Cell Hypoxia - genetics Cell Line, Tumor DEAD-box RNA Helicases - genetics DEAD-box RNA Helicases - metabolism Deregulation Disease Progression Down-Regulation - genetics Epithelial-Mesenchymal Transition - genetics Ets-1 protein Female Gene expression Gene Expression Regulation, Neoplastic Gene regulation Homeostasis Humanities and Social Sciences Humans Hypoxia Maturation Mice, Nude MicroRNAs MicroRNAs - biosynthesis MicroRNAs - genetics miRNA Models, Biological multidisciplinary Neoplasms - drug therapy Neoplasms - genetics Neoplasms - pathology Post-transcription Proto-Oncogene Protein c-ets-1 - genetics Proto-Oncogene Protein c-ets-1 - metabolism Ribonuclease III - genetics Ribonuclease III - metabolism Ribonucleic acid RNA Science siRNA Transcription factors Tumor microenvironment Tumors Vascular Endothelial Growth Factor A - antagonists & inhibitors Vascular Endothelial Growth Factor A - metabolism
ISSN:	2041-1723, 2041-1723
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Shrnutí:	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. MicroRNAs play important roles in the maintenance of cellular homeostasis through the post-transcriptional regulation of gene expression. Here, the authors implicate loss of the miRNA biogenesis factor Drosha and altered miRNA maturation in tumour progression under hypoxic conditions.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 content type line 14 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/ncomms6202