Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/104187
Citations
Scopus Web of Science® Altmetric
?
?
Full metadata record
DC FieldValueLanguage
dc.contributor.authorBhattacharya, S.en
dc.contributor.authorChalk, A.en
dc.contributor.authorNg, A.en
dc.contributor.authorMartin, T.en
dc.contributor.authorZannettino, A.en
dc.contributor.authorPurton, L.en
dc.contributor.authorLu, J.en
dc.contributor.authorBaker, E.en
dc.contributor.authorWalkley, C.en
dc.date.issued2016en
dc.identifier.citationOncogene, 2016; 35(40):5282-5294en
dc.identifier.issn0950-9232en
dc.identifier.issn1476-5594en
dc.identifier.urihttp://hdl.handle.net/2440/104187-
dc.description.abstractOsteosarcoma (OS) is the most common cancer of bone and the 5th leading cause of cancer-related death in young adults. Currently, 5-year survival rates have plateaued at ~70% for patients with localized disease. Those with disseminated disease have an ~20% 5-year survival. An improved understanding of the molecular genetics of OS may yield new approaches to improve outcomes for OS patients. To this end, we applied murine models that replicate human OS to identify and understand dysregulated microRNAs (miRNAs) in OS. miRNA expression patterns were profiled in murine primary osteoblasts, osteoblast cultures and primary OS cell cultures (from primary and paired metastatic locations) isolated from two genetically engineered murine models of OS. The differentially expressed miRNA were further assessed by a cross-species comparison with human osteoblasts and OS cultures. We identified miR-155-5p and miR-148a-3p as deregulated in OS. miR-155-5p suppression or miR-148a-3p overexpression potently reduced proliferation and induced apoptosis in OS cells, yet strikingly, did not impact normal osteoblasts. To define how these miRNAs regulated OS cell fate, we used an integrated computational approach to identify putative candidate targets and then correlated these with the cell biological impact. Although we could not resolve the mechanism through which miR-148a-3p impacts OS, we identified that miR-155-5p overexpression suppressed its target Ripk1 (receptor (TNFRSF)-interacting serine-threonine kinase 1) expression, and miR-155-5p inhibition elevated Ripk1 levels. Ripk1 is directly involved in apoptosis/necroptosis. In OS cells, small interfering RNA against Ripk1 prevented cell death induced by the sequestration of miR-155-5p. Collectively, we show that miR-148a-3p and miR-155-5p are species-conserved deregulated miRNA in OS. Modulation of these miRNAs was specifically toxic to tumor cells but not normal osteoblasts, raising the possibility that these may be tractable targets for miRNA-based therapies for OS.en
dc.description.statementofresponsibilityS Bhattacharya, AM Chalk, AJM Ng, TJ Martin, AC Zannettino, LE Purton, J Lu, EK Baker and CR Walkleyen
dc.language.isoenen
dc.publisherNature Publishing Groupen
dc.rights© 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserveden
dc.subjectCell Line, Tumor; Animals; Humans; Mice; Osteosarcoma; Disease Models, Animal; MicroRNAs; Apoptosis; Cell Differentiation; Cell Proliferation; Gene Expression Regulation, Neoplastic; Receptor-Interacting Protein Serine-Threonine Kinasesen
dc.titleIncreased miR-155-5p and reduced miR-148a-3p contribute to the suppression of osteosarcoma cell deathen
dc.typeJournal articleen
dc.identifier.rmid0030046747en
dc.identifier.doi10.1038/onc.2016.68en
dc.identifier.pubid241983-
pubs.library.collectionMedicine publicationsen
pubs.library.teamDS14en
pubs.verification-statusVerifieden
pubs.publication-statusPublisheden
dc.identifier.orcidZannettino, A. [0000-0002-6646-6167]en
Appears in Collections:Medicine publications

Files in This Item:
There are no files associated with this item.


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.