Pleural mesothelioma (PM) is characterized by rapid growth, local invasion and limited
therapeutic options. The multifunctional oncoprotein Y-box-binding protein-1 (YB-1)
is frequently overexpressed in cancer and its inhibition reduces aggressive behavior
in multiple tumor types. Here, we investigated the effects of YB-1 on target gene
regulation and PM cell behavior. Whereas siRNA-mediated YB-1 knockdown reduced cell
motility, YB-1 overexpression resulted in scattering, increased migration and intravasation
in vitro. Furthermore, YB-1 stimulated PM cell spreading in zebrafish. Combined knockdown
and inducible overexpression of YB-1 allowed bidirectional control and rescue of cell
migration, the pattern of which was closely followed by the mRNA and protein levels
of EGFR and the protein level of Snail, whereas the mRNA levels of MMP1, EPHA5 and
PARK2 showed partial regulation by YB-1. Finally, we identified Snail as a critical
regulator of YB-1-mediated cell motility in PM. This study provides insights into
the mechanism underlying the aggressive nature of PM and highlights the important
role of YB-1 in this cancer. In this context, we found that YB-1 closely regulates
EGFR and Snail, and, moreover, that YB-1-induced cell migration depends on Snail.
