Characterization of the role of the RUNX2 transcriptional regulator in angiogenesis and oncogenic transformation

Abstract

Carcinogenesis is a complex process that is regulated by a variety of host responses, which include neovascularization, or angiogenesis. Vascular endothelial cell (EC) proliferation, migration, and tissue invasion are critical for the establishment of new blood vessels within tumors. These EC functions are under the control of key transcriptional regulators that modulate the expression of angiogenic factors, cytokine receptors, and proteases. The expression and functional role of the transcription factor runt-related gene 2 (RUNX2) has been implicated in a variety of biological and pathological events. The aim of this thesis is to begin to characterize the role of RUNX2 in angiogenesis and oncogenic transformation. A major finding of this study indicates that RUNX2 regulates cell growth arrest, differentiation, apoptosis, and migration of endothelial cells exposed to extracellular matrix (ECM). Each of these biological functions is a critical step in the complex process of angiogenesis. This work has also elucidated a novel function for a naturally occurring splice-variant of RUNX2 that was determined to be a competitive inhibitor of RUNX2, lending further support to the hypothesis that ECs regulate growth and apoptosis through RUNX2 alternative splicing events. Further studies using cultured fibroblasts supported a role for oncogenic transformation through interaction with the YES-associated transcriptional coactivator, YAP. Elucidating the basic mechanisms of RUNX2 gene regulation in the process of angiogenesis may provide potential pharmacological approaches to inhibit angiogenesis and prevent tumor growth and metastasis. Accordingly, determining the mechanism of RUNX2 in oncogenic transformation may similarly lead to novel therapeutic approaches to directly target tumor cells and inhibit the progression of cancer.