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

Autor: Sarah P. Blagden, Sadaf Ghaem-Maghami, Andrea J. Berman, Normala Abd-Latip, Roni M. Lahr, Jennifer H. Steel, Hiba A. Al-Ashtal, Justin Weir, Eric O. Aboagye, Manuela Mura, Mona El-Bahrawy, Haonan Lu, T.G. Hopkins, Katrina Sweeney
Přispěvatelé: Wellbeing of Women, Cancer Research UK, GlaxoSmithKline Services Unlimited, Imperial College Healthcare NHS Trust- BRC Funding, Medical Research Council (MRC), National Institute for Health Research, Scottish Power Foundation, Engineering & Physical Science Research Council (EPSRC), Commission of the European Communities, US Army (US)
Jazyk: angličtina
Rok vydání: 2015
Předmět:
0301 basic medicine
Untranslated region
PROGNOSIS
Carcinogenesis
05 Environmental Sciences
RNA-binding protein
Mice
SCID
medicine.disease_cause
Autoantigens
Mice
Inbred NOD
LA-RELATED PROTEIN
TOOL
Mice
Knockout
Ovarian Neoplasms
Gene knockdown
Microscopy
Confocal
Reverse Transcriptase Polymerase Chain Reaction
3. Good health
Gene Expression Regulation
Neoplastic
Ribonucleoproteins
Disease Progression
Female
RNA Interference
MESSENGER-RNA
Life Sciences & Biomedicine
STEM-CELLS
Interleukin Receptor Common gamma Subunit
Protein Binding
EXPRESSION
Biochemistry & Molecular Biology
Cell Survival
Blotting
Western
Transplantation
Heterologous
BCL-2
Antineoplastic Agents
Biology
03 medical and health sciences
Cell Line
Tumor
Genetics
medicine
Animals
Humans
Molecular Biology
Science & Technology
Gene Expression Profiling
Cancer
06 Biological Sciences
medicine.disease
Survival Analysis
Molecular biology
LARP1
030104 developmental biology
Drug Resistance
Neoplasm
Hela Cells
Cancer cell
MICROARRAY DATA
Cancer research
08 Information and Computing Sciences
TRANSLATION
Ovarian cancer
RESISTANCE
Developmental Biology
Zdroj: Nucleic Acids Research
ISSN: 1362-4962
0305-1048
Popis: 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.
Databáze: OpenAIRE
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