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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.

Original publication

DOI

10.1093/nar/gkv1515

Type

Journal article

Journal

Nucleic Acids Res

Publication Date

18/02/2016

Volume

44

Pages

1227 - 1246

Keywords

Animals, Antineoplastic Agents, Autoantigens, Blotting, Western, Carcinogenesis, Cell Line, Tumor, Cell Survival, Disease Progression, Drug Resistance, Neoplasm, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, HeLa Cells, Humans, Interleukin Receptor Common gamma Subunit, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Microscopy, Confocal, Ovarian Neoplasms, Protein Binding, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Ribonucleoproteins, Survival Analysis, Transplantation, Heterologous