The role of MAPK pathway in bone and soft tissue tumors.

Aim: Expression of mitogen-activated protein kinase (MAPK) signaling and its role in cell proliferation of the bone malignancies, osteosarcoma (OS) and malignant fibrous histiocytoma (MFH) were investigated. Materials and Methods: Gene expression and protein levels of RAF1 and MEK1/2 in 6 human sarcoma cell lines and 7 surgically obtained OS specimens were assessed by RT-PCR and immuno- histochemistry, respectively. MEK inhibitor, U0126 (1,4- diamino-2,3-dicyano-1,4-bis (2-aminophynyltio) butadiene), was used for cell proliferation assays. Results: RAF1 and MEK 1/2 mRNA was detected in all cell lines and OS specimens. RAF1, MEK 1/2 and p-MEK protein was also expressed in the cells, as was MEK1/2 in OS specimens. Treatment with U0126 resulted in dose- and time-dependent inhibition of cell proliferation and suppression of p-ERK expression, opposite to promotion of p-MEK. Conclusion: U0126 blocks MAPK signaling and decreases cell proliferation in OS and MFH. Thus, selective MAPK inhibitors might be therapeutically advantageous in the treatment of bone and soft tissue sarcomas. Osteosarcoma (OS) is a malignant bone tumor that commonly affects adolescents and young adults, accounting for approximately 20% of primary bone malignancies in humans. Malignant fibrous histiocytoma (MFH) is the most common soft tissue sarcoma arising in late adult life. Advances in the treatment of both OS and MFH have led to multidisciplinary treatments that include surgery, chemotherapy and radiation therapy, all of which result in great improvement in the quality of life for patients with sarcomas (1, 2). However, current chemotherapeutic protocols for sarcomas demonstrate poorer results than for other malignancies, with the prognosis of sarcoma patients typically being local recurrence and metastasis. Recently, molecular-targeting drugs have been developed for other human malignancies including cancer and hematopoietic malignancies (3-5). These drugs have selective inhibitory effects on the various factors (including growth factor receptors and intracellular signaling factors) involved in tumor proliferation, migration and metastasis (6). It has previously been reported that overexpression and abnormal activation of growth factors and intracellular signaling factors may be related to tumor proliferation, migration and metastasis in OS and MFH, as well as in other malignancies such as small cell lung cancer, gastrointestinal stromal tumors, pancreatic cancer, cholangiocellular carcinoma, and several types of leukemia (7-11).