Functional analysis of Mirk/Dyrk 1B in osteosarcoma

Osteosarcoma is the most common primary malignant tumor of bone.  Standard treatment is surgery and chemotherapy, which has significantly improved the survival rate from 11% with surgery alone to 60-70% when surgery is combined with chemotherapy.  Unfortunately, progress has been limited over the past 20 years, and the identification of new therapies is critical to improving the survival rate of osteosarcoma patients.  Protein kinases have recently been targeted by pharmaceutical agents to decrease tumor growth (i.e. Bcr-Abl, EGFR, Her2, c-kit).  One of the less known kinases, Mirk/Dyrk1B, is a unique, multifunctional kinase, that has been observed to be amplified, upregulated, or constitutively expressed in several different types of cancer. Previously, we utilized a lentiviral shRNA kinase library to screen osteosarcoma cells and showed that knockdown of Mirk expression inhibits cell growth and induces apoptosis in osteosarcoma cell lines.  We observed that Mirk is commonly overexpressed in osteosarcoma but not in normal osteoblasts. Mrik participates in multiple cellular pathways that enhance tumor growth and survival, and we observed that high levels of Mirk expression in osteosarcoma tissue are associated with more aggressive clinical behavior.  Therefore, our proposed project has the following goals: 1) Determine the impact of overexpression of Mirk in human osteoblast cell lines on cell differentiation, proliferation and neoplastic transformation; and 2) Analyze the molecular consequences of inhibiting Mirk in osteosarcoma cell lines.  Our long term goal is to elucidate the regulatory mechanisms controlling expression of Mirk and ultimately develop therapeutic strategies that can be used to improve the treatment of patients with osteosarcoma.