Abstract 279: A small molecular miR-21 inhibitor inhibits glioma cell invasion and mesenchymal transition via upregulation of VHL expression.

Abstract

Abstract Glioblastomas (GBMs) are the most common malignant brain tumors which characterized by rapid and invasive growth. Accumulating evidence points to a critical role of EMT like events during glioma progression and malignant transformation. Cancer cells undergoing EMT can acquire invasive properties and enter the surrounding stroma, resulting in the creation of a favorable microenvironment for cancer progression and metastasis. In this study, we identified a small molecular miR-21 inhibitor through a high-throught screening approach and found it significantly repressed the U87 and LN229 glioma cell migration and invasion. Meanwhile, VHL, a direct target of miR-21, was increased expression in mRNA and protein level after this miR-21 inhibitor treatment, but the β-catenin expression was reduced. Silencing of VHL using small interefering RNA (siRNA) also reduced β-catenin expression. Furthermore, suppression of β-catenin transactivation by miR-21 inhibitor, through upregulation of VHL expression, increased E-cadherin expression and partially reversed the epithelial-mesenchymal transition (EMT). On the other hand, confocal microscopy and Western blot assay presented that N-cadherin, ZEB1, ZEB2 and MMP9 expression were reduced. Additionally, in a U87 intracranial glioma xenograft nude mice model, we found a less invading tumor edge of miR-21 inhibitor treated group in comparison with DMSO group. Moreover, there was an increased expression of E-cadherin and reduced expression of β-catenin, N-cadherin, ZEB1, ZEB2 and MMP9 in tumor samples after the inhibitor treatment. Together, these results provided insight into the specific treatment efficacy of this small molecular inhibitor in EMT and tumor metastasis, which achieved via up-regulation of VHL expression. Therefore, it might be a novel and potentially antimetastatic agent for therapeutic intervention in glioblastomas in future. Citation Format: Zhendong Shi, Junxia Zhang, Lei Han, Kailiang Zhang, Luyue Chen, Xiaomin Qian, Peiyu Pu, Chunsheng Kang. A small molecular miR-21 inhibitor inhibits glioma cell invasion and mesenchymal transition via upregulation of VHL expression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 279. doi:10.1158/1538-7445.AM2013-279