Muñoz-Hidalgo Lisandra, San-Miguel Teresa, Megías Javier, Serna Eva, Calabuig-Fariñas Silvia, Monleón Daniel, Gil-Benso Rosario, Cerdá-Nicolás Miguel, López-Ginés Concha
INCLIVA, Clinic Hospital of Valencia, 46010 Valencia, Spain.
Department of Pathology, Faculty of Medicine and Dentistry, University of Valencia, 46010 Valencia, Spain.
Int J Mol Sci. 2020 Dec 31;22(1):368. doi: 10.3390/ijms22010368.
Migration of glioblastoma cells into surrounding tissue is one of the main features that makes this tumor incurable. We evaluated whole-genome miRNA expression profiling associated with different EGFR amplification patterns in 30 cases of primary glioblastoma. From the 64 miRNAs that showed differential expression between tumors with a high level of EGFR amplification and tumors without EGFR amplification, 40% were related with cell migration, being miR-200c the most differentially expressed between these two groups. We investigated the effect of miR-200c on ZEB1 expression and cell migration in an in vitro transfection model with a miR-200c mimic, a miR-200c inhibitor and siRNA targeting EGFR in three short-term cultures with different levels of EGFR amplification obtained from resected glioblastomas. The cell culture with the highest EGFR amplification level presented the lowest miR-200c expression and the status of EGFR modulated the effect of miR-200c on ZEB1 expression. Silencing EGFR led to miR-200c upregulation and ZEB1 downregulation in transfected cultures, except in the presence of high levels of EGFR. Likewise, miR-200c upregulation decreased ZEB1 expression and inhibited cell migration, especially when EGFR was not amplified. Our results suggest that modulating miR-200c may serve as a novel therapeutic approach for glioblastoma depending on EGFR status.
胶质母细胞瘤细胞向周围组织的迁移是导致这种肿瘤难以治愈的主要特征之一。我们评估了30例原发性胶质母细胞瘤中与不同表皮生长因子受体（EGFR）扩增模式相关的全基因组微小RNA（miRNA）表达谱。在高水平EGFR扩增的肿瘤与无EGFR扩增的肿瘤之间表现出差异表达的64种miRNA中，40%与细胞迁移相关，其中miR-200c在这两组之间的差异表达最为明显。我们在一个体外转染模型中研究了miR-200c对锌指E盒结合蛋白1（ZEB1）表达和细胞迁移的影响，该模型使用miR-200c模拟物、miR-200c抑制剂以及针对EGFR的小干扰RNA（siRNA），这些实验在从切除的胶质母细胞瘤中获得的具有不同EGFR扩增水平的三种短期培养物中进行。EGFR扩增水平最高的细胞培养物中miR-200c表达最低，并且EGFR的状态调节了miR-200c对ZEB1表达的影响。在转染的培养物中，沉默EGFR导致miR-200c上调和ZEB1下调，但在EGFR高水平存在的情况下除外。同样，miR-200c上调降低了ZEB1表达并抑制了细胞迁移，特别是当EGFR未扩增时。我们的结果表明，根据EGFR状态，调节miR-200c可能成为胶质母细胞瘤的一种新的治疗方法。
