title: Small RNA sequencing and functional characterization reveals MicroRNA-143 tumor suppressor activity in liposarcoma.
abstract: Liposarcoma remains the most common mesenchymal cancer, with a mortality rate of 60% among patients with this disease. To address the present lack of therapeutic options, we embarked upon a study of microRNA (miRNA) expression alterations associated with liposarcomagenesis with the goal of exploiting differentially expressed miRNAs and the gene products they regulate as potential therapeutic targets. MicroRNA expression was profiled in samples of normal adipose tissue, well-differentiated liposarcoma, and dedifferentiated liposarcoma by both deep sequencing of small RNA libraries and hybridization-based Agilent microarrays. The expression profiles discriminated liposarcoma from normal adipose tissue and well differentiated from dedifferentiated disease. We defined over 40 miRNAs that were dysregulated in dedifferentiated liposarcomas in both the sequencing and the microarray analysis. The upregulated miRNAs included two cancer-associated species (miR-21 and miR-26a), and the downregulated miRNAs included two species that were highly abundant in adipose tissue (miR-143 and miR-145). Restoring miR-143 expression in dedifferentiated liposarcoma cells inhibited proliferation, induced apoptosis, and decreased expression of BCL2, topoisomerase 2A, protein regulator of cytokinesis 1 (PRC1), and polo-like kinase 1 (PLK1). The downregulation of PRC1 and its docking partner PLK1 suggests that miR-143 inhibits cytokinesis in these cells. In support of this idea, treatment with a PLK1 inhibitor potently induced G(2)-M growth arrest and apoptosis in liposarcoma cells. Taken together, our findings suggest that miR-143 re-expression vectors or selective agents directed at miR-143 or its targets may have therapeutic value in dedifferentiated liposarcoma.
authors.affiliation: Department of Surgery, Sarcoma Biology Laboratory, Sarcoma Disease Management Program, The Rockefeller University, New York, New York, USA.
authors.forename: Stacy
authors.initials: S
authors.lastname: Ugras
authors.forename: Elliott
authors.initials: E
authors.lastname: Brill
authors.forename: Anders
authors.initials: A
authors.lastname: Jacobsen
authors.forename: Markus
authors.initials: M
authors.lastname: Hafner
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Socci
authors.forename: Penelope L
authors.initials: PL
authors.lastname: Decarolis
authors.forename: Raya
authors.initials: R
authors.lastname: Khanin
authors.forename: Rachael
authors.initials: R
authors.lastname: O'Connor
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Mihailovic
authors.forename: Barry S
authors.initials: BS
authors.lastname: Taylor
authors.forename: Robert
authors.initials: R
authors.lastname: Sheridan
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Gimble
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.forename: Aimee
authors.initials: A
authors.lastname: Crago
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.forename: Thomas
authors.initials: T
authors.lastname: Tuschl
authors.forename: Samuel
authors.initials: S
authors.lastname: Singer
mesh_terms: D050156:Adipogenesis / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048749:Cytokinesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008080:Liposarcoma / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D035683:MicroRNAs / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; C542359:MIRN143 microRNA, human; D035683:MicroRNAs; C116662:PRC1 protein, human