Kong Jienan, Di Chunchan, Piao Junjie, Sun Jie, Han Longzhe, Chen Liyan, Yan Guanghai, Lin Zhenhua
Department of Pathology and Cancer Research Center, Yanbian University Medical College, Yanji 133002, China.
Department of Pathology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
Oncotarget. 2016 Apr 12;7(15):19631-42. doi: 10.18632/oncotarget.7779.
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.
宫颈癌是全球女性中第三大常见癌症。晚期宫颈癌的治疗选择有限，导致死亡率很高。埃兹蛋白是一种最近报道的膜细胞骨架结合蛋白，可作为肿瘤促进因子，我们之前指出埃兹蛋白的异常定位和过表达可能是宫颈癌预后评估的一个独立有效生物标志物。在本研究中，我们确定埃兹蛋白是宫颈癌上皮-间质转化（EMT）和转移的调节因子。埃兹蛋白敲低在体外和体内均抑制了宫颈癌细胞系的非锚定依赖性生长、细胞迁移和侵袭。在埃兹蛋白缺失的细胞中EMT受到抑制，E-钙黏蛋白和细胞角蛋白-18（CK-18）上调，间充质标志物下调。埃兹蛋白敲低还诱导了Akt磷酸化。这些结果表明埃兹蛋白是宫颈癌中的一种EMT调节因子和肿瘤促进因子，埃兹蛋白的下调可能通过磷酸肌醇3-激酶/Akt途径抑制宫颈癌进展。此外，通过免疫组织化学检测，埃兹蛋白的表达模式与宫颈癌的淋巴管浸润状态密切相关，生存分析显示，核周埃兹蛋白表达模式的宫颈癌患者比细胞质埃兹蛋白表达模式的患者生存时间更长。因此，埃兹蛋白是开发旨在预防宫颈癌进展的新型有效策略的一个有前景的靶点。
