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The RNA-binding protein LARP1 is a post-transcriptional regulator of survival and tumorigenesis in ovarian cancer.

Authors
  • Hopkins, Thomas G1
  • Mura, Manuela1
  • Al-Ashtal, Hiba A2
  • Lahr, Roni M2
  • Abd-Latip, Normala1
  • Sweeney, Katrina1
  • Lu, Haonan1
  • Weir, Justin3
  • El-Bahrawy, Mona3
  • Steel, Jennifer H4
  • Ghaem-Maghami, Sadaf1
  • Aboagye, Eric O5
  • Berman, Andrea J6
  • Blagden, Sarah P7
  • 1 Ovarian Cancer Action Research Centre, Institute of Reproductive and Developmental Biology, Imperial College, London W12 0HS, UK.
  • 2 Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
  • 3 Department of Histopathology, Imperial College Healthcare NHS Trust, London W12 0NN, UK.
  • 4 Imperial College Experimental Cancer Medicine Centre, Division of Cancer, Imperial College Academic Health Science Centre, London W12 0NN, UK.
  • 5 Comprehensive Cancer Imaging Centre, Imperial College, Du Cane Road, London W12 0NN, UK.
  • 6 Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA [email protected]
  • 7 Ovarian Cancer Action Research Centre, Institute of Reproductive and Developmental Biology, Imperial College, London W12 0HS, UK Department of Oncology, University of Oxford, Old Road, Oxford OX3 7LE, UK [email protected]
Type
Published Article
Journal
Nucleic Acids Research
Publisher
Oxford University Press
Publication Date
Feb 18, 2016
Volume
44
Issue
3
Pages
1227–1246
Identifiers
DOI: 10.1093/nar/gkv1515
PMID: 26717985
Source
Medline
License
Unknown

Abstract

RNA-binding proteins (RBPs) are increasingly identified as post-transcriptional drivers of cancer progression. The RBP LARP1 is an mRNA stability regulator, and elevated expression of the protein in hepatocellular and lung cancers is correlated with adverse prognosis. LARP1 associates with an mRNA interactome that is enriched for oncogenic transcripts. Here we explore the role of LARP1 in epithelial ovarian cancer, a disease characterized by the rapid acquisition of resistance to chemotherapy through the induction of pro-survival signalling. We show, using ovarian cell lines and xenografts, that LARP1 is required for cancer cell survival and chemotherapy resistance. LARP1 promotes tumour formation in vivo and maintains cancer stem cell-like populations. Using transcriptomic analysis following LARP1 knockdown, cross-referenced against the LARP1 interactome, we identify BCL2 and BIK as LARP1 mRNA targets. We demonstrate that, through an interaction with the 3' untranslated regions (3' UTRs) of BCL2 and BIK, LARP1 stabilizes BCL2 but destabilizes BIK with the net effect of resisting apoptosis. Together, our data indicate that by differentially regulating the stability of a selection of mRNAs, LARP1 promotes ovarian cancer progression and chemotherapy resistance.

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