Ezrin contributes to cervical cancer progression through induction of epithelial-mesenchymal transition

Abstract

// Jienan Kong 1, 2 * , Chunchan Di 3, * , Junjie Piao 1 , Jie Sun 1 , Longzhe Han 4 , Liyan Chen 1 , Guanghai Yan 1 , Zhenhua Lin 1 1 Department of Pathology and Cancer Research Center, Yanbian University Medical College, Yanji 133002, China 2 Department of Pathology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China 3 Department of Pathology, Zibo First Hospital, Zibo 255200, China 4 Department of Pathology, Yanbian University Hospital, Yanji 133000, China * These authors contributed equally to this work Correspondence to: Zhenhua Lin, e-mail: zhlin720@ybu.edu.cn Guanghai Yan, e-mail: ghyan@ybu.edu.cn Keywords: Ezrin, epithelial-mesenchymal transition, invasion, metastasis, uterine cervical cancer Received: June 18, 2015      Accepted: February 10, 2016      Published: February 27, 2016 ABSTRACT Cervical cancer is the third most common cancer in females worldwide. The treatment options for advanced cervical cancer are limited, leading to high mortality. Ezrin is a membrane-cytoskeleton-binding protein recently reported to act as a tumor promoter, and we previously indicated that the aberrant localization and overexpression of Ezrin could be an independent effective biomarker for prognostic evaluation of cervical cancers. In this study, we identified Ezrin as a regulator of epithelial-mesenchymal transition (EMT) and metastasis in cervical cancer. Ezrin knock-down inhibited anchorage-independent growth, cell migration, and invasion of cervical cancer cell lines in vitro and in vivo . EMT was inhibited in Ezrin-depleted cells, with up-regulation of E-cadherin and Cytokeratin-18 (CK-18) and down-regulation of mesenchymal markers. Ezrin knock-down also induced Akt phosphorylation. These results implicate Ezrin as an EMT regulator and tumor promoter in cervical cancer, and down-regulation of Ezrin suppressed cervical cancer progression, possibly via the phosphoinositide 3-kinase/Akt pathway. Furthermore, the expression pattern of Ezrin protein was closely related with the lymphovascular invasion status of cervical cancer by immunohistochemistry, and the survival analysis revealed that the cervical cancer patients with the perinuclear Ezrin expression pattern had longer survival time than those with the cytoplasmic Ezrin expression pattern. Ezrin thus represents a promising target for the development of novel and effective strategies aimed at preventing the progression of cervical cancer.