Abstract

Neogenin-1, is a transmembrane receptor involved in axonal guidance, angiogenesis, neuronal cell migration, and cell death. Neogenin-1 bound to the Netrin and RGM ligand families during development and adult homeostasis. While Neogenin-1 and its ligands have been shown to be involved in tumor progression, little is known about the specific function of the proteins and the cell signaling events that occur in cancer cells. Clinical analysis of neuroblastoma primary tumor public database of Neogenin-1 and Netrin-4 indicates that high levels of mRNA of both molecules have poor overall survival rate. In this cancer, the function the function of these proteins is not known and in this work, we are going to determine Neogenin-1 and its autocrine ligand Netrin-4 function in cell migration, proliferation, survival and metastasis, the main aspects of tumor progression. Neogenin-1 knockdown reduces cell migration and the silencing of endogenous Netrin-4 reduces cell migration, proliferation and cell survival. In the other hand, when Neogenin-1 is overexpressed, cells migrate more in the presence of Netrin-4 along with increased apoptosis. This augmented apoptosis is avoided using exogenous Netrin-4 at physiological concentrations. Metastasis analysis using in vivo chorioallantoic membrane (CAM) of chicken embryos, shows that Neogenin-1 and endogenous Netrin-4 participates in the metastasis process. Then, when Netrin-4 binds Neogenin-1, cell migration starts, and when this interaction is avoided, apoptosis is activated. Thus, endogenous Netrin-4 maintains the cells in both, a pro-survival and pro-migratory state.