title: LMTK3 escapes tumour suppressor miRNAs via sequestration of DDX5.
abstract: Lemur tyrosine kinase-3 (LMTK3) plays an important role in cancer progression and is associated with breast, lung, gastric and colorectal cancer. MicroRNAs (miRNAs) are small endogenous non-coding RNAs that typically repress target genes at post-transcriptional level and have an important role in tumorigenesis. By performing a miRNA expression profile, we identified a subset of miRNAs modulated by LMTK3. We show that LMTK3 induces miR-34a, miR-196-a2 and miR-182 levels by interacting with DEAD-box RNA helicase p68 (DDX5). LMTK3 binds via DDX5 to the pri-miRNA of these three mature miRNAs, thereby sequestrating them from further processing. Ectopic expression of miR-34a and miR-182 in LMTK3-overexpressing cell lines (MCF7-LMTK3 and MDA-MB-231-LMTK3) inhibits breast cancer proliferation, invasion and migration. Interestingly, miR-34a and miR-182 directly bind to the 3'UTR of LMTK3 mRNA and consequently inhibit both its stability and translation, acting as tumour suppressor-like miRNAs. In aggregate, we show that LMTK3 is involved in miRNA biogenesis through modulation of the Microprocessor complex, inducing miRNAs that target LMTK3 itself.
authors.affiliation: Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK. Electronic address: j.jacob@imperial.ac.uk.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Jacob
authors.affiliation: Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Rosy
authors.initials: R
authors.lastname: Favicchio
authors.affiliation: Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Negin
authors.initials: N
authors.lastname: Karimian
authors.affiliation: Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Maryam
authors.initials: M
authors.lastname: Mehrabi
authors.affiliation: Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Harding
authors.affiliation: Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Leandro
authors.initials: L
authors.lastname: Castellano
authors.affiliation: Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Justin
authors.initials: J
authors.lastname: Stebbing
authors.affiliation: Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK; Department of Biochemistry and Biomedicine, School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK. Electronic address: g.giamas@sussex.ac.uk.
authors.forename: Georgios
authors.initials: G
authors.lastname: Giamas
mesh_terms: D020413:3' Untranslated Regions; D001665:Binding Sites; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; C542543:MIRN196 microRNA, human; C522425:MIRN34 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C538984:Mirn182 microRNA, human; C560359:LMTK3 protein, human; D017346:Protein Serine-Threonine Kinases; C506749:Ddx5 protein, human; D053487:DEAD-box RNA Helicases
keywords: DDX5; LMTK3; miR-182; miR-196a; miR-34a; miRNA processing