Abstract
Osteosarcoma (OS) is the most common primary tumor of bone in children and adolescents. It is highly aggressive and thought to arise primarily from osteoblasts (OB), bone-forming cells. Radiation exposure is the most significant environmental risk factor for OS. OS occurs as a secondary tumor after the radiotherapy, and is also known to be induced following the incorporation of bone-seeking alpha emitters. However, the genes and signaling pathways involved in radiation-induced OS are not fully understood. Using oligonucleotide microarrays, we profiled gene expression in rat OS tumors induced by the bone-seeking alpha emitter 238Pu and compared these expression profiles to those of normal OB. The expressions of 72 genes were significantly differentially expressed in the OS related to OB samples. These included genes involved in the cell adhesion, tumor-suppressor function, differentiation, developmental processes, Src tyrosine kinase and Wnt/β-catenin signaling pathways. Expression changes of several genes were validated by quantitative real-time RT-PCR analysis. Constitutive activation of the Wnt/β-catenin signaling pathway in the tumors was suggested by the transcriptome analysis and confirmed by observing nuclear and/or cytoplasmic localization of β-catenin in the tumors using immunohistochemistry. In addition, we found a decrease of the glycogen synthase kinase 3β (GSK-3β) and the inactive (phosphorylated) form of β-catenin in the tumor relative to OB samples by immunoblot analysis.
