The long-term objective of this application is to understand the regulatory mechanisms by which Wnt signaling inhibits apoptosis and promotes tumorigenesis. The Wnt family genes encode a group of secretory glycoproteins that play important roles in embryogenesis, cell proliferation, and specification of cell fate. Aberrant activation of the Wnt signaling pathway is often correlated with the over-expression or amplification of the c-myc oncogene and associated with numerous human cancers including colorectal cancer, breast cancer and squamous cell carcinoma. Although significant progress has been made in understanding the Wnt signaling cascade, little is known about the Wnt-mediated survival as well as oncogenic cooperation between Wnt and c-Myc. The preliminary studies from our laboratory have found that constitutive activation of Wnt signaling inhibits chemotherapeutic drug-induced apoptosis in vitro by inhibiting cytochrome c release and caspase-9 activation. Wnt signaling cooperates with c-Myc in oncogenic transformation by inhibiting apoptosis. To further understand the molecular mechanism of Wnt-mediated oncogenesis and survival, we propose three specific aims. Given the fact that the anoikis resistance plays a critical role in oncogenic transformation and invasive growth of epithelial cancer cells, in Aim 1, we will extend our previous works by determining whether Wnt signaling inhibits anoikis or tumor necrosis factor/c-Myc-mediated apoptosis. To fully understand Wnt-mediated survival and oncogenic cooperation between c-Myc and Wnt, in Aim 2, we will attempt to identify novel anti-apoptotic genes induced by the Wnt signaling pathway using a combination of microarray analysis and functional assays.
In Aim 3, we will characterize novel components of the canonical Wnt signaling pathways and determine their role in Wnt-mediated survival and oncogenesis.
These aims are integrated and are important in understanding the regulatory mechanism of oncogensis and apoptosis by the Wnt signaling pathway. The findings from this proposal will yield new insights into Wnt-associated human cancer and provide the molecular basis for human cancer treatment.
