Chen Le, Yao Ying, Sun Lijuan, Zhou Jiajia, Miao Minmin, Luo Shujuan, Deng Guanming, Li Junjun, Wang Jing, Tang Jie
Department of Gynecologic Oncology, Hunan Cancer Hospital, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
Department of gynecology and obstetrics, the First People's Hospital of Yueyang, Yueyang, China.
Cell Physiol Biochem. 2017;43(6):2489-2504. doi: 10.1159/000484458. Epub 2017 Oct 31.
BACKGROUND/AIMS: Our study aims to investigate the role, effect and mechanisms of ESRP1 (epithelial splicing regulatory protein 1) in epithelial-mesenchymal transition (EMT) in epithelial ovarian cancer (EOC).
Microarray and immunohistochemical analysis of ESRP1 expression were performed in EOC cases. The correlations between ESRP1 expression and clinical factors on EOC were assessed. Lentivirus-mediated RNA interference and EGFP vector which contains ESRP1 gene were used to down-regulate and up-regulate ESRP1 expression in human EOC cell lines. Roles of ESRP1 in cell growth, migration and invasion of EOC cells were also measured by Cell Counting Kit-8 and Transwell systems in vitro and by a nude mice intraperitoneal transplantation model in vivo.
By the analysis of Gene Expression Omnibus (GEO) (p<0.05) and our own microarray data (p<0.001), ESRP1 expression in EOC was significantly different from normal ovarian tissue. It was abundant in the nuclei of cancer cells and in malignant lesions. However, it was weakly expressed or negative in both normal and benign lesions. High ESRP1 expression in EOC was associated with poor clinical outcomes. Decreased ESRP1 expression significantly increased cell migration and invasion both in vivo and in vitro. Snail strongly repressed ESRP1 transcription through binding to the ESRP1 promoter in EOC cells. Furthermore, ESRP1 regulated the expression of CD44s. Down-regulated ESRP1 resulted in an isoform switching from CD44v to CD44s, which modulated epithelial-mesenchymal transition (EMT) program in EOC. Up-regulatin of ESRP1 was detected in mesenchymal to epithelial transition (MET) in vivo.
ESRP1 regulates CD44 alternative splicing during the EMT process which plays an important role in EOC carcinogenesis. In addition, ESRP1 is associated with disease prognosis in EOC.
背景/目的：本研究旨在探讨上皮剪接调节蛋白1（ESRP1）在卵巢上皮性癌（EOC）上皮-间质转化（EMT）中的作用、影响及机制。
对EOC病例进行ESRP1表达的基因芯片和免疫组化分析。评估ESRP1表达与EOC临床因素之间的相关性。利用慢病毒介导的RNA干扰和含ESRP1基因的EGFP载体，在人EOC细胞系中下调和上调ESRP1表达。还通过细胞计数试剂盒-8和体外Transwell系统以及体内裸鼠腹腔移植模型，检测ESRP1在EOC细胞生长、迁移和侵袭中的作用。
通过基因表达综合数据库（GEO）分析（p<0.05）和我们自己的基因芯片数据（p<0.001），EOC中ESRP1表达与正常卵巢组织有显著差异。它在癌细胞核和恶性病变中丰富。然而，在正常和良性病变中均弱表达或呈阴性。EOC中ESRP1高表达与不良临床结局相关。ESRP1表达降低显著增加体内和体外细胞迁移和侵袭。Snail通过与EOC细胞中ESRP1启动子结合强烈抑制ESRP1转录。此外，ESRP1调节CD44s的表达。ESRP1下调导致异构体从CD44v转换为CD44s，从而调节EOC中的上皮-间质转化（EMT）程序。在体内间充质向上皮转化（MET）过程中检测到ESRP1上调。
ESRP1在EMT过程中调节CD44可变剪接，这在EOC致癌过程中起重要作用。此外，ESRP1与EOC疾病预后相关。
