title: Down-regulation of MicroRNAs (MiRs) 203, 887, 3619 and 182 Prevents Vimentin-triggered, Phospholipase D (PLD)-mediated Cancer Cell Invasion.
abstract: Breast cancer is a leading cause of morbidity and mortality among women. Metastasis is initiated after epithelial-mesenchymal-transition (EMT). We have found a connection between EMT markers and the expression of four microRNAs (miRs) mediated by the signaling enzyme phospholipase D (PLD). Low aggressive MCF-7 breast cancer cells have low endogenous PLD enzymatic activity and cell invasion, concomitant with high expression of miR-203, -887, and -3619 (that decrease PLD2 translation and a luciferase reporter) and miR-182 (targeting PLD1) that are, therefore, "tumor-suppressor-like" miRs. The combination miR-887+miR-3619 abolished >90% of PLD enzymatic activity. Conversely, post-EMT MDA-MB-231 cells have low miR expression, high levels of PLD1/2, and high aggressiveness. The latter was reversed by ectopically transfecting the miRs, which was negated by silencing miRs with specific siRNAs. We determined that the molecular mechanism is that E-cadherin triggers expression of the miRs in pre-EMT cells, whereas vimentin dampens expression of the miRs in post-EMT invasive cells. This novel work identifies for the first time a set of miRs that are activated by a major pre-EMT marker and deactivated by a post-EMT marker, boosting the transition from low invasion to high invasion, as mediated by the key phospholipid metabolism enzyme PLD.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Wright State University Boonshoft School of Medicine, Dayton, Ohio 45435 and.
authors.forename: Kristen
authors.initials: K
authors.lastname: Fite
authors.affiliation: From the Department of Biochemistry and Molecular Biology, Wright State University Boonshoft School of Medicine, Dayton, Ohio 45435 and Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women Hospital and Harvard Medical School, Boston Massachusetts 02115 julian.cambronero@wright.edu.
authors.forename: Julian
authors.identifier: http://orcid.org/0000-0002-7581-9227
authors.initials: J
authors.lastname: Gomez-Cambronero
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D017124:Conserved Sequence / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D010641:Phenotype; D010739:Phospholipase D / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D014408:Biomarkers, Tumor; D035683:MicroRNAs; D012333:RNA, Messenger; D014746:Vimentin; D010739:Phospholipase D
keywords: chemotaxis; microRNA (miRNA); phospholipid; phosphorylation; signal transduction