miR-181 subunits enhance the chemosensitivity of temozolomide by Rap1B-mediated cytoskeleton remodeling in glioblastoma cells
miR-181 subunits enhance the chemosensitivity of temozolomide by Rap1B-mediated cytoskeleton remodeling in glioblastoma cells
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DOI：
10.1007/s12032-014-0892-9
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发表时间：
2014-04-01
期刊：
影响因子：
3.4
通讯作者：
Wu, Minghua
中科院分区：
文献类型：
--
作者：
She, Xiaoling;Yu, Zhibin;Wu, Minghua
多形性胶质母细胞瘤(GBM)是最恶性和最常见的脑肿瘤，其生长方式具有侵袭性，尽管治疗方法最好，但预后较差。尽管替莫唑胺(TMZ)化疗可能会在几个月内抑制肿瘤生长，但TMZ耐药性也很常见，是许多治疗失败的原因。对microRNA在GBM中作用的研究表明，microRNAs在GBM中起着关键的调节作用，使其成为潜在的治疗靶点。在本研究中，我们证实了miR-181a/b/c/d亚基的低表达参与了星形细胞瘤的发生，其过度表达可以通过靶向Rap1B介导的细胞骨架重构和相关分子(CDC42、RhoA和N-钙粘素)的变化来抑制胶质母细胞瘤细胞的侵袭性增殖，提示miR-181是一个关键的调节因子，可能是胶质母细胞瘤治疗的重要靶点。TMZ作为治疗胶质母细胞瘤的标准化疗药物，通过上调miR-181a/b/c/d亚基，抑制Rap1B表达和肌动蛋白细胞骨架重塑，发挥细胞杀伤作用，反之，各miR-181a/b/c/d亚基均可增强TMZ对胶质母细胞瘤细胞的化疗敏感性。
Glioblastoma multiforme (GBM) is the most malignant and frequent brain tumor, with an aggressive growth pattern and poor prognosis despite best treatment modalities. Although chemotherapy with temozolomide (TMZ) may restrain tumor growth for some months, TMZ resistance is also common and accounts for many treatment failures. Research into microRNA's role in GBM has shown that microRNAs play a key regulatory role in the GBM, making it a potential therapeutic target. In this study, we demonstrated that the lower expression of miR- 181a/b/c/d subunits contributes to astrocytoma tumorigenesis, and their overexpression could inhibit the invasive proliferation of glioblastoma cells by targeting Rap1B-mediated cytoskeleton remodeling and related molecular (Cdc42, RhoA and N- cadherin) changes, suggesting that miR- 181 was a critical regulator and might be an important target for glioblastoma treatment. TMZ as a standard chemotherapeutic agent for GBM inhibited the Rap1B expression and actin cytoskeleton remodeling to exert its cell killing by upregulating miR- 181a/b/c/d subunits; conversely, each miR- 181a/ b/ c/ d subunit enhanced the chemosensitivity of TMZ in glioblastoma cells.