Abstract
Aim: Osteosarcomas represent the most common primary malignant bone tumors. However, their pathogenesis is unclear. In vitro and in vivo studies have demonstrated the participation of the JNK–c-Jun signal transduction cascade and oncoproteins c-Jun and c-Fos in osteoblast proliferation and differentiation. JNKs activate c-Jun, which forms the AP-1 transcription factor as a homo/heterodimeric complex. Alpha-NAC is an osteo-blast-specific AP-1 coactivator that potentiates c-Jun/c-Jun, but not c-Jun/c-Fos transcriptional activity. We addressed the possibility that upregulation of the JNK–c-Jun pathway, as well as expression/activation of c-Fos and á-NAC, are implicated in osteosarcoma pathogenesis.
Materials and method: We assessed immunohistochemically the protein levels of the two major JNK isoforms (JNK1,2), their phosphorylated/activated species, p-JNK, their substrate, c-Jun, its phosphorylated/activated form, pc-Jun, its partner, c-Fos, and á-NAC, in 71 human osteo-sarcomas (56 high and 15 low grade).
Results: Positive immunostaining for JNK1, JNK2, p-JNK, c-Jun, pc-Jun, c-Fos and á-NAC was observed in 86%, 93%, 94%, 99%, 97%, 99% and 97.5% of the samples, respectively, but not in normal bone. Cellular levels of all proteins were significantly correlated to each other (p< 0.001). Moreover, significantly higher expression levels of all proteins were detected in high-grade osteosarcomas, compared to low-grade ones (p< 0.001).
Discussion: Our findings provide novel evidence that the JNK–AP-1 pathway is involved in osteoblast malignant transformation and osteosarcoma development and progression. Furthermore, the expression profile of α-NAC suggests that the active AP-1 population in human osteosarcomas is most likely comprised of c-Jun/c-Jun homodimers. Evaluation of c-Jun expression and JNK-dependent activation may facilitate an improved prediction of tumors’ clinical behaviour and potentially be exploited in designing patient-tailored treatment regimens.
The abstracts were prepared by Eleni Koutsoukou. Correspondence should be addressed to him at the Hellenic Association of Orthopaedic Surgery and Traumatology (HAOST), 20, A. Fleming str, 15123 Marousi, Athens, Greece.
