EphA2 promotes tumorigenicity of cervical cancer by up‐regulating CDK6

Abstract

Erythropoietin‐producing hepatocellular receptor A2 (EphA2) receptor tyrosine kinase plays an important role in tissue organization and homeostasis in normal organs. EphA2 is overexpressed in a variety of types of solid tumours with oncogenic functions. However, the role of EphA2 in cervical cancer (CC) is still needed to be further explored. Here, we examined the role of EphA2 by establishing a stable EphA2 knock‐down CC cell lines or a stable EphA2‐overexpressed CC cells lines. Overexpression of EphA2 increased cell proliferation and migration of CC while EphA2 knock‐down decreased the CC tumorigenicity. In addition, EphA2 knock‐down suppressed CC tumour development in the xenograft mouse model. Inhibition of EphA2 by AWL‐II‐41‐27, EphA2‐specific tyrosine kinase inhibitor, or knock‐down of EphA2 decreased mRNA and protein expression of cyclin‐dependent kinase (CDK) 6 in CC cells, which increased cellular susceptibility to epirubicin (EPI), an anti‐cancer chemotherapy drug. A clinicopathological study of EphA2 was conducted on a cohort of 158 human CC patients. EphA2 protein expression was positively correlated with CDK6 protein expression, invasion depth, lymph node metastasis and clinicopathological stage (P < .05). This study demonstrates the oncogenic activity of EphA2 in vitro and in vivo, which provides insights into the relevant mechanisms that might lead to novel treatments for CC.

The EPH/Ephrin System in Gynecological Cancers: Focusing on the Roots of Carcinogenesis for Better Patient Management

“…EPHA2 protein expression exhibited upregulation in CC cell lines, leading to increased cell proliferation and migration of CC. EPHA2 knockdown increased the cellular susceptibility to epirubicin in CC cells and suppressed CC growth in a xenograft mouse model [ 69 ].…”

High-Risk Human Papillomavirus and Epstein–Barr Virus Coinfection: A Potential Role in Head and Neck Carcinogenesis

“…A high level of CD21 was found in HPV+/EBV+ NPCs, when compared to EBV-/HPV- tumors ( p = 0.0194), although no difference was observed between HPV+/EBV+ NPCs and those harboring EBV or HPV single infections [ 7 ]. Furthermore, increased levels of EphA2, the epithelial EBV receptor, was evidenced in CIN and cervical carcinomas when compared to normal cervical epithelium, and also correlated with CDK6 protein expression [ 123 ]. In addition, a 15.28-fold increase in EphA2 receptor expression was observed in non-tumor cervical cells transfected with the HPV18 E2 gene [ 124 ].…”

circ‐ZNF609: A potent circRNA in human cancers

“…In present, studies have confirmed that high‐risk human papillomavirus (HPV) infection is the main cause of CC, about 95% of CC is related to HPV infection, leading to precancerous lesions and invasion of CC 67 . Recently, NF‐YA and EphA2 were identified as key regulators in the pathogenesis of CC, without detailed exploration in the clinical setting 68,69 . Therefore, it is of great clinical significance to deeply explore the pathogenesis of CC and find more potential molecular markers of CC.…”

“… 67 Recently, NF‐YA and EphA2 were identified as key regulators in the pathogenesis of CC, without detailed exploration in the clinical setting. 68 , 69 Therefore, it is of great clinical significance to deeply explore the pathogenesis of CC and find more potential molecular markers of CC.…”