Regulation of neuroblastoma migration, invasion, and in vivo metastasis by genetic and pharmacological manipulation of MDA-9/Syntenin.

摘要: Despite multi-modality treatments, prognosis for advanced stage neuroblastoma (NB) remains challenging with residual long-term disabilities in survivors. Advanced NB is metastatic, which a principal cause of cancer-related deaths. We presently document primary role MDA-9 progression and define the molecular mechanisms by promotes transformed phenotypes. cell lines clinical samples display elevated expression bioinformatic analysis supports an association between bone metastasis poor prognosis. Genetic (shmda-9, mda-9 siRNA) or pharmacological (small molecule inhibitor protein-protein interactions; PDZ1i) blockade decreases migration, invasion, metastasis. Blocking disrupting partner protein interactions downregulates integrin α6 β4, diminishing Src activity suppressing Rho-Rac-Cdc42 activity. These signaling changes inhibit cofilin matrix metalloproteinases reducing vitro vivo migration. Overexpression β4 rescues invasion phenotype increases activity, supporting integrins as essential regulators MDA-9-mediated migration invasion. identify key contributor to pathogenesis show that genetic inhibition suppresses integrin-mediated Src-disruption pathway.