Role and prognostic significance of the epithelial-mesenchymal transition factor ZEB2 in ovarian cancer.
Role and prognostic significance of the epithelial-mesenchymal transition factor ZEB2 in ovarian cancer.
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DOI：
10.18632/oncotarget.3943
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发表时间：
2015-08-07
期刊：
影响因子：
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通讯作者：
Ferlini C
中科院分区：
文献类型：
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作者：
Prislei S;Martinelli E;Zannoni GF;Petrillo M;Filippetti F;Mariani M;Mozzetti S;Raspaglio G;Scambia G;Ferlini C
ZEB 2是上皮-间质转化（EMT）的关键因子，EMT是控制胚胎发育和成人组织稳态中细胞迁移的程序。我们证明了ZEB 2在卵巢癌中的迁移和锚定非依赖性细胞生长中的作用，如ZEB 2沉默所示。我们发现RNA结合蛋白HuR与ZEB 2 mRNA的3′UTR结合，作为ZEB 2蛋白表达的正调控因子。在Hey卵巢细胞系中，HuR沉默降低了ZEB 2和ZEB 1的核表达并损害了迁移。在低血糖条件下，ZEB 2表达下降，沿着ZEB 1、波形蛋白和细胞质HuR，并且观察到细胞迁移能力降低。对卵巢癌中ZEB 2和HuR表达的分析显示，细胞核ZEB 2定位于肿瘤前缘，并与细胞质HuR共定位。在一系列143名卵巢癌患者中，ZEB 2 mRNA的高表达与总生存率和无进展生存率方面的不良预后显著相关。此外，在免疫组化评价中，我们发现ZEB 2蛋白的预后意义依赖于其核表达和与细胞质HuR的共定位。总之，我们的研究结果表明，核ZEB 2可能会促进卵巢癌EMT转变和获得侵袭性表型的进展。
ZEB2 is a key factor in epithelial-mesenchymal transition (EMT), a program controlling cell migration in embryonic development and adult tissue homeostasis. We demonstrated a role of ZEB2 in migration and anchorage-independent cell growth in ovarian cancer, as shown by ZEB2 silencing. We found that the RNA-binding protein HuR bound the 3′UTR of ZEB2 mRNA, acting as a positive regulator of ZEB2 protein expression. In Hey ovarian cell line, HuR silencing decreased ZEB2 and ZEB1 nuclear expression and impaired migration. In hypoglycemic conditions ZEB2 expression decreased, along with ZEB1, vimentin and cytoplasmic HuR, and a reduced cellular migration ability was observed. Analysis of ZEB2 and HuR expression in ovarian cancers revealed that nuclear ZEB2 is localized in tumor leading edge and co-localizes with cytoplasmic HuR. In a series of 143 ovarian cancer patients high expression of ZEB2 mRNA significantly correlated with a poor prognosis in term of both overall survival and progression- free survival. Moreover, at immunohistochemical evaluation, we found that prognostic significance of ZEB2 protein relies on its nuclear expression and co-localization with cytoplasmic HuR. In conclusion our findings indicated that nuclear ZEB2 may enhance progression of EMT transition and acquisition of an aggressive phenotype in ovarian cancer.