The overexpression of EPS8L1 upregulates TIAM2 to promote cytoskeleton remodeling by activating the Rac1/MAPK signaling pathway in the migration of ovarian cancer

Abstract

Background: EPS8L1, an analog of epidermal growth factor receptor pathway substrate 8 (Eps8), was screened out in our previous work from clinical samples of patients with ovarian cancer. We also found that EPS8L1 was involved in various biological activities. In this study, the participation and mechanisms of EPS8L1 ion the migration and metastasis of ovarian cancer were investigated. Methods: In vitro scratch-healing, transwell assay, and actin-staining studies were performed in SKOV-3 ovarian cancer cells with EPS8L1 overexpression or knockdown. An ovarian cancer mouse model with lung colonization was established to evaluate the in vivo colonization and migration. To identify correlated proteins, a bioinformatics assay was conducted and verified via qRT-PCR and Western blot. Results: EPS8L1 knockdown inhibited cellular migration in vitro and reduced tumor colonization in vivo. The actin-staining and ELISA experiments suggested that EPS8L1 regulated actin formation as well as cytoskeleton remodeling. Furthermore, mRNA and protein expression confirmed that EPS8L1 regulated the downstream T-cell lymphoma invasion and metastasis 2 (TIAM2) molecule and stimulated the activation of Rac1. Additionally, the phosphorylation levels of P38, Erk, and Jnk in the MAPK pathway decreased after EPS8L1 knockdown. Conclusions: The upregulation of EPS8L1 could promote the migration and metastasis of ovarian cancer cells by regulating cytoskeleton remodeling. The mechanism underlying this might be that EPS8L1 regulates TIAM2 to induce the transformation of Rac-GDP into Rac-GTP and then activates the downstream MAPK pathway. As a regulatory factor in cell migration and metastasis, EPS8L1 could be a new prognostic biomarker and a promising therapeutic target for ovarian cancer patients.