EphB2 promotes cervical cancer progression by inducing epithelial-mesenchymal transition

Abstract

EphB2, a receptor tyrosine kinase for ephrin ligands, is overexpressed in various cancers and plays an important role in tumor progression. However, the expression and functions of EphB2 in cervical cancer remain unknown. In this study, we performed immunohistochemistry in clinical cervical specimens and found that EphB2 was overexpressed in the cervical cancer specimens, and its expression correlated with cancer progression. The percentage of EphB2-positive cells increased gradually from 28% in the normal cervix to 40% in high-grade squamous intraepithelial lesions, and ultimately to 69.8% in squamous cell carcinomas (P < .05). We overexpressed EphB2 in HeLa cells and silenced EphB2 in cervical cancer (C33A) cells, which expressed low and high levels of EphB2, respectively. Exogenous EphB2 promoted cell migration, invasion, and an epithelial-mesenchymal transition (EMT) signature, which is a complex process that occurs during organogenesis and cancer metastasis, whereas EphB2 silencing had the opposite effect (P < .05). Furthermore, HeLa cells with exogenous EphB2 exhibited a stem cell-like state that promoted tumorsphere formation in vitro and exhibited tumorigenesis potential in vivo (P < .05), whereas EphB2 silencing in C33A cells inhibited these stem cell properties (P < .05). In addition, we investigated the intracellular signaling pathways in cervical cancer and found that R-Ras expression correlated positively with EphB2 in clinical samples, and its activity was regulated by EphB2 in cervical cancer. These findings demonstrate that EphB2 plays an important role in cervical cancer progression by orchestrating an EMT program through R-Ras activation.