Downregulation of miR-21 inhibits EGFR pathway and suppresses the growth of human glioblastoma cells independent of PTEN status
Downregulation of miR-21 inhibits EGFR pathway and suppresses the growth of human glioblastoma cells independent of PTEN status
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miR-21 的下调抑制 EGFR 通路并抑制人胶质母细胞瘤细胞的生长，与 PTEN 状态无关
DOI：
10.1038/labinvest.2009.126
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发表时间：
2010-02-01
影响因子：
5
通讯作者：
Kang, Chunsheng
中科院分区：
文献类型：
--
作者：
Zhou, Xuan;Ren, Yu;Kang, Chunsheng
MicroRNA (miRNA) 是一类内源性小非编码 RNA，在转录后调节基因表达。 miRNA 的异常表达已被证明与肿瘤发生有关。我们发现 miR-21 是人胶质母细胞瘤 (GBM) 细胞系中最常过度表达的 miRNA 之一。为了探讨 miR-21 是否可以作为胶质母细胞瘤的治疗靶点，我们用特定的反义寡核苷酸下调 miR-21，发现 U251（PTEN 突变型）和 LN229（PTEN 野生型）GBM 细胞在体外诱导细胞凋亡并抑制细胞周期进展；反义处理的 U251 细胞的异种移植肿瘤在体内受到抑制。反义 miR-21 处理的细胞显示 EGFR、激活的 Akt、细胞周期蛋白 D 和 Bcl-2 的表达降低。尽管已知 miR-21 可以调节 PTEN，并且 miR-21 的下调会导致内源性和报告基因测定中 PTEN 表达增加，但反义 miR-21 的 GBM 抑制作用很可能独立于 PTEN 调节，因为 U251 具有突变的 PTEN。微阵列分析表明，miR-21 的敲低显着改变了涉及 9 个细胞周期和信号通路的 169 个基因的表达。总而言之，我们的研究提供了证据，表明 miR-21 可能作为独立于 PTEN 状态的恶性神经胶质瘤的新治疗靶点。
MicroRNAs (miRNAs) are a class of endogenous small noncoding RNAs that regulate gene expression after transcription. Aberrant expression of miRNAs has been shown to be involved in tumorigenesis. We showed that miR-21 was one of the most frequently overexpressed miRNA in human glioblastoma (GBM) cell lines. To explore whether miR-21 can serve as a therapeutic target for glioblastoma, we downregulated miR-21 with a specific antisense oligonucleotide and found that apoptosis was induced and cell-cycle progression was inhibited in vitro in U251 (PTEN mutant) and LN229 (PTEN wild-type) GBM cells; xenograft tumors from antisense-treated U251 cells were suppressed in vivo. Antisense-miR-21-treated cells showed a decreased expression of EGFR, activated Akt, cyclin D, and Bcl-2. Although miR-21 is known to regulate PTEN and downregulation of miR-21 led to increased PTEN expression both endogenously and in a reporter gene assay, the GBM suppressor effect of antisense-miR-21 is most likely independent of PTEN regulation because U251 has mutant PTEN. Microarray analysis showed that the knockdown of miR-21 significantly altered expression of 169 genes involved in nine cell-cycle and signaling pathways. Taken together, our studies provide evidence that miR-21 may serve as a novel therapeutic target for malignant gliomas independent of PTEN status.