p21-activated kinase 4 regulation of endometrial cancer cell migration and invasion involves the ERK1/2 pathway mediated MMP-2 secretion.

Endometrial cancer (EC) is one of the most common malignancy of the female genital tract. Patients with metastatic disease have a poor prognosis. So far, however, the underlying molecular mechanisms of EC metastasis are largely unknown. P21-activated kinase 4 (Pak4) is important in cell motility and oncogenesis. Here we investigated a role of Pak4 in EC cell migration and invasion. Pak4 overexpression was observed in multiple human EC cell lines. In clinical samples, expression of total and phosphorylated Pak4 (Pak4 and p-Pak4, respectively) increased significantly with progression of EC from normal tissue to lymph node metastasis; both were positively correlated with depth of myometrial and vascular space invasion, lymph nodes metastasis, and poor histological differentiation. In two human EC cell lines, Pak4 overexpression promoted cell migration and invasion in vitro. Short hairpin RNA (shRNA)-mediated stable knockdown of Pak4 inhibited the metastatic potential of EC in an ERK1/2-MMP-2-dependent manner. These results suggest that Pak4 is an important regulator of EC cell migration and invasion. Therefore, Pak4 may be a promising target for the treatment of metastatic EC.