|Public on Dec 31, 2013
|Effect of LOX-PP on the gene expression profile of the A673 cell line (Ewing sarcoma)
|Expression profiling by array
|In this study we show that lysyl oxidase (LOX), an enzyme involved in maintaining structural integrity of the extracellular matrix, is expressed at low levels in Ewing sarcoma cells and primary tumors and is downregulated by the EWS/FLI1 oncoprotein characteristic of these tumors. Using a doxycycline inducible system to restore LOX expression in an Ewing sarcoma derived cell line, we show that LOX displays tumor suppressor activities. Interestingly, we show that the tumor suppressor activity resides in the propeptide domain of LOX (LOX-PP), an N-terminal domain produced by proteolytic cleavage during the physiological processing of LOX. Finally, we show that LOX-PP inhibits ERK/MAPK signalling pathway, and that many pathways involved in cell cycle progression were significant deregulated by LOX-PP, providing a mechanistic explanation to the cell proliferation inhibition observed upon LOX-PP expression. In summary, our observations indicate that deregulation of the LOX gene participates in Ewing sarcoma development and identify LOX-PP as a new therapeutic target for one of the most aggressive paediatric malignancies. These findings suggest that therapeutic strategies based in the administration of LOX propeptide or functional analogues could be useful in the treatment of this devastating paediatric cancer.
|A673 cells derived from Ewing sarcoma were genetically enginereed to express LOX-PP upon doxycycline stimulation (72 hours). Three independent experiments from control cells and three independent experiments from A673 cells expressing LOX-PP were done. Gene expression profile in A673 cells expressing LOX-PP vs control cells were compared.
|Agra N, Cidre F, Alonso J
|Apr 26, 2013
|Last update date
|Feb 10, 2020
|INSTITUTO DE SALUD CARLOS III - IIER
|AREA DE GENÉTICA HUMANA
|UNIDAD DE TUMORES SOLIDOS INFANTILES
|CTRA. MAJADAHONDA-POZUELO KM 2
|Agilent-039494 SurePrint G3 Human GE v2 8x60K Microarray 039381 (Probe Name version)