DESCRIPTION (provided by applicant):
Lung cancer is the leading cause of cancer mortality and metastasizes to the bone, adrenal glands, liver, small intestine, and brain. Bone morphogenetic protein-3B (BMP-3B), a tumor suppressor gene, has been shown to be silenced in lung cancer. Importantly, BMP-3B is found to be down regulated in all non small cell lung cancer patient samples and cell lines. Our preliminary data provide evidence that Runx2, an essential transcription factor for bone development and linked metastatic bone diseases, is a potent suppressor of BMP-3B. We show that Runx2-/- mice exhibit higher levels of BMP-3B than WT and over expression of Runx2 represses BMP-3B gene transcription. Oncogenic properties of Runx2 have been demonstrated in transgenic mice where Runx2 over expression perturbs T- cell development and synergizes strongly with c-myc in lymphomagenesis. Recent studies from our group and others show that Runx2 promotes osteolytic lesions associated with cancer by regulating transcription of metastatic genes (MMP9, MMP13 and VEGF) and oncogenes. Based on these observations, we hypothesize that Runx2 is involved in lung cancer progression. Consistent with this concept, we find increased Runx2 expression in lung cancer cells compared to normal lung fibroblasts. However, role of Runx2 in lung cancer has not been studied. We propose to address the hypothesis that Runx2 regulates tumor suppressors (e.g., BMP-3B) and/or oncogenes to contribute to lung cancer progression. Specific aims of this proposal are: 1) determining the expression pattern of Runx2 in relation with stages of lung cancer; 2) establishing tumor suppressor candidate gene BMP-3B is a direct target of Runx2 and examining the effect of Runx2 depletion on tumorigenic properties of lung cancer cells; 3) generation and characterization of stable cells with altered levels of Runx2 or BMP-3B to understand lung cancer progression and bone metastasis. We seek to understand the molecular regulatory mechanism of genome wide gene regulation by Runx2 by modulating its levels in vivo model and will identify novel Runx2 target genes (tumor suppressor or oncogenes) in lung cancer. Identifying the role for Runx2 in transcriptional regulation together with TGF-beta/BMP signaling will enhance our understanding of requirement of stringent regulation of gene transcription and its perturbation in lung cancer cells that may be translated to novel therapies for lung cancer
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