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miR-873 通过靶向 Bcl-2 充当胶质细胞瘤细胞对顺铂的新型增敏剂。

MiR-873 acts as a novel sensitizer of glioma cells to cisplatin by targeting Bcl-2.

机构信息

School of Basic Medical Sciences, Wuhan University, Wuhan 430071, P.R. China.

Department of Neurosurgery, Wuhan University Renmin Hospital, Wuhan 430071, P.R. China.

出版信息

Int J Oncol. 2015 Oct;47(4):1603-11. doi: 10.3892/ijo.2015.3143. Epub 2015 Aug 31.

Abstract

Treatment with cisplatin, a chemotherapeutic agent commonly used in glioma patients, often results in chemoresistance. Increasing evidence has shown that microRNAs (miRNAs) are implicated in the drug resistance of gliomas. However, the function of miR‑873 in cisplatin resistance of gliomas remains unknown. In this study, we found that many miRNAs, including miR‑873, are differentially expressed in cisplatin-resistant glioma cells compared to wild-type glioma cells. Moreover, cisplatin reduced the expression of miR‑873 in a time-dependent manner. Overexpression of miR‑873 decreased the cell proliferation, migration and invasion while increased apoptosis of cisplatin-resistant glioma cells and sensitized the cells to cisplatin-induced cell growth arrest and apoptosis. Furthermore, miR‑873 was downregulated while Bcl-2 was upregulated in the tissues of twelve high-grade glioma patients compared to seven normal brain tissues, and the miR‑873 level was negatively correlated with the Bcl-2 protein level. A luciferase reporter assay further confirmed that Bcl-2 was a direct target of miR‑873, and miR‑873 decreased the level of the Bcl-2 protein in cisplatin-resistant glioma cells. Notably, re-expression of Bcl-2 attenuated the function of miR‑873 in cisplatin-resistant glioma cells and the sensitivity of the cells to cisplatin. Taken together, these data suggest that miR‑873 might be a potential marker for cisplatin resistance and a promising sensitizer in cisplatin treatment.

摘要

顺铂治疗,一种常用于神经胶质瘤患者的化疗药物,常导致化疗耐药。越来越多的证据表明,microRNAs(miRNAs)参与神经胶质瘤的耐药性。然而,miR-873 在神经胶质瘤顺铂耐药中的作用尚不清楚。在本研究中,我们发现许多 miRNAs,包括 miR-873,在顺铂耐药神经胶质瘤细胞中与野生型神经胶质瘤细胞相比存在差异表达。此外,顺铂以时间依赖性方式降低 miR-873 的表达。miR-873 的过表达降低了顺铂耐药神经胶质瘤细胞的增殖、迁移和侵袭能力,同时增加了细胞凋亡,并使细胞对顺铂诱导的细胞生长停滞和凋亡敏感。此外,与 7 例正常脑组织相比,在 12 例高级别神经胶质瘤患者的组织中 miR-873 下调而 Bcl-2 上调,并且 miR-873 水平与 Bcl-2 蛋白水平呈负相关。荧光素酶报告基因检测进一步证实 Bcl-2 是 miR-873 的直接靶标,并且 miR-873 降低了顺铂耐药神经胶质瘤细胞中 Bcl-2 蛋白的水平。值得注意的是,Bcl-2 的重新表达减弱了 miR-873 在顺铂耐药神经胶质瘤细胞中的作用及其对顺铂的敏感性。总之,这些数据表明 miR-873 可能是顺铂耐药的潜在标志物和顺铂治疗的有前途的增敏剂。

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