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

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-AguayoLi Huang, Menashe Bar-Eli, Bradly G Wouters, Milan Radovich, Mircea Ivan, George A Calin, Wei Zhang, Gabriel Lopez-Berestein, Anil K Sood^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	5202
Journal	Nature Communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms6202
Publication status	Published - 2014

Keywords

Animals
Cell 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

Access to Document

10.1038/ncomms6202

Cite this

Rupaimoole, R., Wu, S. Y., Pradeep, S., Ivan, C., Pecot, C. V., Gharpure, K. M., Nagaraja, A. S., Armaiz-Pena, G. N., McGuire, M., Zand, B., Dalton, H. J., Filant, J., Miller, J. B., Lu, C., Sadaoui, N. C., Mangala, L. S., Taylor, M., van den Beucken, T., Koch, E., ... Sood, A. K. (2014). Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression. Nature Communications, 5, Article 5202. https://doi.org/10.1038/ncomms6202

@article{34cb710e22e3418a9dd292a0d00aba22,

title = "Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression",

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.",

keywords = "Animals, Cell 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",

author = "Rajesha Rupaimoole and Wu, {Sherry Y} and Sunila Pradeep and Cristina Ivan and Pecot, {Chad V} and Gharpure, {Kshipra M} and Nagaraja, {Archana S} and Armaiz-Pena, {Guillermo N} and Michael McGuire and Behrouz Zand and Dalton, {Heather J} and Justyna Filant and Miller, {Justin Bottsford} and Chunhua Lu and Sadaoui, {Nouara C} and Mangala, {Lingegowda S} and Morgan Taylor and {van den Beucken}, Twan and Elizabeth Koch and Cristian Rodriguez-Aguayo and Li Huang and Menashe Bar-Eli and Wouters, {Bradly G} and Milan Radovich and Mircea Ivan and Calin, {George A} and Wei Zhang and Gabriel Lopez-Berestein and Sood, {Anil K}",

year = "2014",

doi = "10.1038/ncomms6202",

language = "English",

volume = "5",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

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, AK 2014, 'Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression', Nature Communications, vol. 5, 5202. https://doi.org/10.1038/ncomms6202

TY - JOUR

T1 - Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression

AU - Rupaimoole, Rajesha

AU - Wu, Sherry Y

AU - Pradeep, Sunila

AU - Ivan, Cristina

AU - Pecot, Chad V

AU - Gharpure, Kshipra M

AU - Nagaraja, Archana S

AU - Armaiz-Pena, Guillermo N

AU - McGuire, Michael

AU - Zand, Behrouz

AU - Dalton, Heather J

AU - Filant, Justyna

AU - Miller, Justin Bottsford

AU - Lu, Chunhua

AU - Sadaoui, Nouara C

AU - Mangala, Lingegowda S

AU - Taylor, Morgan

AU - van den Beucken, Twan

AU - Koch, Elizabeth

AU - Rodriguez-Aguayo, Cristian

AU - Huang, Li

AU - Bar-Eli, Menashe

AU - Wouters, Bradly G

AU - Radovich, Milan

AU - Ivan, Mircea

AU - Calin, George A

AU - Zhang, Wei

AU - Lopez-Berestein, Gabriel

AU - Sood, Anil K

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Hypoxia

KW - Cell Line, Tumor

KW - DEAD-box RNA Helicases

KW - Disease Progression

KW - Down-Regulation

KW - Epithelial-Mesenchymal Transition

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Mice, Nude

KW - MicroRNAs

KW - Models, Biological

KW - Neoplasms

KW - Proto-Oncogene Protein c-ets-1

KW - Ribonuclease III

KW - Vascular Endothelial Growth Factor A

U2 - 10.1038/ncomms6202

DO - 10.1038/ncomms6202

M3 - Article

C2 - 25351346

SN - 2041-1723

VL - 5

JO - Nature Communications

JF - Nature Communications

M1 - 5202

ER -