Girdin regulates both migration and angiogenesis in pancreatic cancer cell lines

Girdin, an actin-binding protein, is reportedly involved in the invasion and angiogenesis of various cancers. It has been suggested that the flavonoid Scutellarin (SCU) inhibits Girdin signaling. In the present study, the function and therapeutic applications of Girdin in pancreatic cancer (PaCa) were investigated. Immunohistochemical staining of Girdin in resected PaCa specimens from the Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Science showed that high Girdin expression was associated with poor overall survival and relapse-free survival, as well as with T factor, indicating invasion into the surrounding tissues. On the other hand, Girdin was highly expressed in almost all PaCa cell lines, and the migration ability of Girdin-knockdown cell lines was decreased even under epidermal growth factor (EGF) stimulation. In addition, SCU suppressed PaCa cell migration by inhibiting the phosphorylation of Girdin. The expression and production of vascular endothelial growth factor A (VEGF-A) was significantly decreased in Girdin-knockdown cell lines. Furthermore, in Matrigel tube formation assays performed using culture supernatant, the lumen-forming ability of vascular endothelial cells was also decreased in Girdin-knockdown cell lines. However, SCU treatment did not significantly alter the expression or production of VEGF-A. These results suggested that Girdin is involved in EGF signaling-mediated migration of PaCa cells, that SCU inhibits PaCa invasion by suppressing Girdin activity, and that Girdin is also involved in angiogenesis via an activation pathway different from the action site of SCU. Girdin may be a prognostic biomarker, and the development of a novel molecular-targeted drugs for Girdin may improve the prognosis of PaCa in the future.