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dc.contributor.authorKuijjer, Marieke Len_US
dc.contributor.authorvan den Akker, Brendy EWMen_US
dc.contributor.authorHilhorst, Rieten_US
dc.contributor.authorMommersteeg, Moniqueen_US
dc.contributor.authorBuddingh, Emilie Pen_US
dc.contributor.authorSerra, Massimoen_US
dc.contributor.authorBürger, Horsten_US
dc.contributor.authorHogendoorn, Pancras CWen_US
dc.contributor.authorCleton-Jansen, Anne-Marieen_US
dc.date.accessioned2014-03-11T13:52:43Z
dc.date.issued2014en_US
dc.identifier.citationKuijjer, Marieke L, Brendy EWM van den Akker, Riet Hilhorst, Monique Mommersteeg, Emilie P Buddingh, Massimo Serra, Horst Bürger, Pancras CW Hogendoorn, and Anne-Marie Cleton-Jansen. 2014. “Kinome and mRNA expression profiling of high-grade osteosarcoma cell lines implies Akt signaling as possible target for therapy.” BMC Medical Genomics 7 (1): 4. doi:10.1186/1755-8794-7-4. http://dx.doi.org/10.1186/1755-8794-7-4.en
dc.identifier.issn1755-8794en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:11879794
dc.description.abstractBackground: High-grade osteosarcoma is a primary malignant bone tumor mostly occurring in adolescents and young adults, with a second peak at middle age. Overall survival is approximately 60%, and has not significantly increased since the introduction of neoadjuvant chemotherapy in the 1970s. The genomic profile of high-grade osteosarcoma is complex and heterogeneous. Integration of different types of genome-wide data may be advantageous in extracting relevant information from the large number of aberrations detected in this tumor. Methods: We analyzed genome-wide gene expression data of osteosarcoma cell lines and integrated these data with a kinome screen. Data were analyzed in statistical language R, using LIMMA for detection of differential expression/phosphorylation. We subsequently used Ingenuity Pathways Analysis to determine deregulated pathways in both data types. Results: Gene set enrichment indicated that pathways important in genomic stability are highly deregulated in these tumors, with many genes showing upregulation, which could be used as a prognostic marker, and with kinases phosphorylating peptides in these pathways. Akt and AMPK signaling were identified as active and inactive, respectively. As these pathways have an opposite role on mTORC1 signaling, we set out to inhibit Akt kinases with the allosteric Akt inhibitor MK-2206. This resulted in inhibition of proliferation of osteosarcoma cell lines U-2 OS and HOS, but not of 143B, which harbors a KRAS oncogenic transformation. Conclusions: We identified both overexpression and hyperphosphorylation in pathways playing a role in genomic stability. Kinome profiling identified active Akt signaling, which could inhibit proliferation in 2/3 osteosarcoma cell lines. Inhibition of PI3K/Akt/mTORC1 signaling may be effective in osteosarcoma, but further studies are required to determine whether this pathway is active in a substantial subgroup of this heterogeneous tumor.en
dc.language.isoen_USen
dc.publisherBioMed Centralen
dc.relation.isversionofdoi:10.1186/1755-8794-7-4en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3932036/pdf/en
dash.licenseLAAen_US
dc.subjectOsteosarcomaen
dc.subjectTumor cell linesen
dc.subjectKinome profilingen
dc.subjectGene expression profilingen
dc.subjectGenomic instabilityen
dc.subjectBone tumoren
dc.titleKinome and mRNA expression profiling of high-grade osteosarcoma cell lines implies Akt signaling as possible target for therapyen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalBMC Medical Genomicsen
dash.depositing.authorKuijjer, Marieke Len_US
dc.date.available2014-03-11T13:52:43Z
dc.identifier.doi10.1186/1755-8794-7-4*
dash.contributor.affiliatedKuijjer, Marieke


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