title: The RNA-binding protein LARP1 is a post-transcriptional regulator of survival and tumorigenesis in ovarian cancer.
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.
authors.affiliation: Ovarian Cancer Action Research Centre, Institute of Reproductive and Developmental Biology, Imperial College, London W12 0HS, UK.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Hopkins
authors.affiliation: Ovarian Cancer Action Research Centre, Institute of Reproductive and Developmental Biology, Imperial College, London W12 0HS, UK.
authors.forename: Manuela
authors.initials: M
authors.lastname: Mura
authors.affiliation: Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Hiba A
authors.initials: HA
authors.lastname: Al-Ashtal
authors.affiliation: Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Roni M
authors.initials: RM
authors.lastname: Lahr
authors.affiliation: Ovarian Cancer Action Research Centre, Institute of Reproductive and Developmental Biology, Imperial College, London W12 0HS, UK.
authors.forename: Normala
authors.initials: N
authors.lastname: Abd-Latip
authors.affiliation: Ovarian Cancer Action Research Centre, Institute of Reproductive and Developmental Biology, Imperial College, London W12 0HS, UK.
authors.forename: Katrina
authors.initials: K
authors.lastname: Sweeney
authors.affiliation: Ovarian Cancer Action Research Centre, Institute of Reproductive and Developmental Biology, Imperial College, London W12 0HS, UK.
authors.forename: Haonan
authors.initials: H
authors.lastname: Lu
authors.affiliation: Department of Histopathology, Imperial College Healthcare NHS Trust, London W12 0NN, UK.
authors.forename: Justin
authors.initials: J
authors.lastname: Weir
authors.affiliation: Department of Histopathology, Imperial College Healthcare NHS Trust, London W12 0NN, UK.
authors.forename: Mona
authors.initials: M
authors.lastname: El-Bahrawy
authors.affiliation: Imperial College Experimental Cancer Medicine Centre, Division of Cancer, Imperial College Academic Health Science Centre, London W12 0NN, UK.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Steel
authors.affiliation: Ovarian Cancer Action Research Centre, Institute of Reproductive and Developmental Biology, Imperial College, London W12 0HS, UK.
authors.forename: Sadaf
authors.initials: S
authors.lastname: Ghaem-Maghami
authors.affiliation: Comprehensive Cancer Imaging Centre, Imperial College, Du Cane Road, London W12 0NN, UK.
authors.forename: Eric O
authors.initials: EO
authors.lastname: Aboagye
authors.affiliation: Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA AJB190@pitt.edu.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Berman
authors.affiliation: 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 sarah.blagden@oncology.ox.ac.uk.
authors.forename: Sarah P
authors.initials: SP
authors.lastname: Blagden
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001324:Autoantigens / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D018613:Microscopy, Confocal; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012261:Ribonucleoproteins / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis; D014183:Transplantation, Heterologous; D000097585:SS-B Antigen
chemical_list: D000970:Antineoplastic Agents; D001324:Autoantigens; D053631:Interleukin Receptor Common gamma Subunit; D012261:Ribonucleoproteins; D000097585:SS-B Antigen; C507942:Il2rg protein, mouse