Snail Driving Alternative Splicing of CD44 by ESRP1 Enhances Invasion and Migration in Epithelial Ovarian Cancer

被引:57
作者
Chen, Le [1 ]
Yao, Ying [2 ]
Sun, Lijuan [1 ]
Zhou, Jiajia [1 ]
Miao, Minmin [1 ]
Luo, Shujuan [1 ]
Deng, Guanming [1 ]
Li, Junjun [3 ]
Wang, Jing [1 ]
Tang, Jie [1 ]
机构
[1] Cent South Univ, Xiangya Sch Med, Affiliated Canc Hosp, Dept Gynecol Oncol,Hunan Canc Hosp, Changsha, Hunan, Peoples R China
[2] First Peoples Hosp Yueyang, Dept Gynecol & Obstet, Yueyang, Peoples R China
[3] Cent South Univ, Affiliated Canc Hosp, Xiangya Sch Med, Dept Pathol,Hunan Canc Hosp, Changsha, Hunan, Peoples R China
基金
中国国家自然科学基金;
关键词
Epithelial ovarian cancer; ESRP1; EMT; CD44; Invasion and migration; MESENCHYMAL TRANSITION; PANCREATIC-CANCER; REGULATORY PROTEIN-1; COLORECTAL-CANCER; CELL-GROWTH; EXPRESSION; METASTASIS;
D O I
10.1159/000484458
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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). Methods: 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. Results: 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. Conclusions: 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. (C) 2017 The Author(s) Published by S. Karger AG, Basel
引用
收藏
页码:2489 / 2504
页数:16
相关论文
共 42 条
[1]  
[Anonymous], 2020, NCCN Clinical Practice Guidelines in Oncology: Survivorship
[2]   Transitions between epithelial and mesenchymal states in development and disease [J].
Baum, Buzz ;
Settleman, Jeffrey ;
Quinlan, Margaret P. .
SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY, 2008, 19 (03) :294-308
[3]   Mechanisms of alternative pre-messenger RNA splicing [J].
Black, DL .
ANNUAL REVIEW OF BIOCHEMISTRY, 2003, 72 :291-336
[4]   Gene expression profiling supports the hypothesis that human ovarian surface epithelia are multipotent and capable of serving as ovarian cancer initiating cells [J].
Bowen, Nathan J. ;
Walker, L. DeEtte ;
Matyunina, Lilya V. ;
Logani, Sanjay ;
Totten, Kimberly A. ;
Benigno, Benedict B. ;
McDonald, John F. .
BMC MEDICAL GENOMICS, 2009, 2
[5]   EMT and MET in Metastasis: Where Are the Cancer Stem Cells? [J].
Brabletz, Thomas .
CANCER CELL, 2012, 22 (06) :699-701
[6]   CD44 splice isoform switching in human and mouse epithelium is essential for epithelial-mesenchymal transition and breast cancer progression [J].
Brown, Rhonda L. ;
Reinke, Lauren M. ;
Damerow, Mann S. ;
Perez, Denise ;
Chodosh, Lewis A. ;
Yang, Jing ;
Cheng, Chonghui .
JOURNAL OF CLINICAL INVESTIGATION, 2011, 121 (03) :1064-1074
[7]   Clinical implication of the serum galectin-1 expression in epithelial ovarian cancer patients [J].
Chen, Le ;
Yao, Ying ;
Sun, Lijuan ;
Zhou, Jiajia ;
Liu, Jingshi ;
Wang, Jing ;
Li, Junjun ;
Tang, Jie .
JOURNAL OF OVARIAN RESEARCH, 2015, 8
[8]   Epithelial splicing regulatory protein 1 and 2 paralogues correlate with splice signatures and favorable outcome in human colorectal cancer [J].
Deloria, Abigail J. ;
Hoeflmayer, Doris ;
Kienzl, Philip ;
Lopatecka, Justyna ;
Sampl, Sandra ;
Klimpfinger, Martin ;
Braunschmid, Tamara ;
Bastian, Fabienne ;
Lu, Lingeng ;
Marian, Brigitte ;
Staettner, Stefan ;
Holzmann, Klaus .
ONCOTARGET, 2016, 7 (45) :73800-73816
[9]   A Blockade of IGF Signaling Sensitizes Human Ovarian Cancer Cells to the Anthelmintic Niclosamide-Induced Anti-Proliferative and Anticancer Activities [J].
Deng, Youlin ;
Wang, Zhongliang ;
Zhang, Fugui ;
Qiao, Min ;
Yan, Zhengjian ;
Wei, Qiang ;
Wang, Jing ;
Liu, Hao ;
Fan, Jiaming ;
Zou, Yulong ;
Liao, Junyi ;
Hu, Xue ;
Chen, Liqun ;
Yu, Xinyi ;
Haydon, Rex C. ;
Luu, Hue H. ;
Qi, Hongbo ;
He, Tong-Chuan ;
Zhang, Junhui .
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY, 2016, 39 (03) :871-888
[10]   Splicing factor ratio as an index of epithelial-mesenchymal transition and tumor aggressiveness in breast cancer [J].
Fici, Pietro ;
Gallerani, Giulia ;
Morel, Anne-Pierre ;
Mercatali, Laura ;
Ibrahim, Toni ;
Scarpi, Emanuela ;
Amadori, Dino ;
Puisieux, Alain ;
Rigaud, Michel ;
Fabbri, Francesco .
ONCOTARGET, 2017, 8 (02) :2423-2436