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 |
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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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