YB-1通过激活MDM2/p53信号通路来调节胶质瘤细胞的耐药性。

YB-1 modulates the drug resistance of glioma cells by activation of MDM2/p53 pathway.

作者信息

Tong Hui, Zhao Kai, Zhang Jingyu, Zhu Jinxin, Xiao Jianqi

机构信息

Department of Neurosurgery, Linyi Central Hospital, Linyi, Shandong 276400, People's Republic of China.

Department of Neurosurgery, The First Hospital of Qiqihar City, Qiqihar, Heilongjiang 161005, People's Republic of China,

出版信息

Drug Des Devel Ther. 2019 Jan 14;13:317-326. doi: 10.2147/DDDT.S185514. eCollection 2019.

BACKGROUND

Y-box-binding protein-1 (YB-1) is aberrantly expressed in a variety of cancers. However, the biological functional role of YB-1 in glioma is not yet clear.

METHODS

The expression of MDM2 and YB-1 was analyzed by real time PCR. Overexpression and knockdown of YB-1 in glioma cells were created by transfection of pcDNA-YB-1 and siRNA against YB-1, respectively. Cell viability was performed by CCK8 assay.

RESULTS

Our findings showed that glioma tissues had higher expressions of YB-1 than that in cancer-free tissues in 54 glioma patients, which were also positively correlated with Murine MDM2 expression. Overexpression of YB-1 or MDM2 renders a drug resistance feature in glioma cell exposed to temozolomide (TMZ), by directly targeting p53. Genetic or chemical inhibition of MDM2 significantly blocked YB-1-modulated response of glioma cells to TMZ. Moreover, inhibition of YB-1 or MDM2 reduced glioma cells metastasis and mortality in mice.

CONCLUSION

YB-1 facilitates the resistance of glioma cells to TMZ by direct activation of MDM2/p53 signaling and represents a promising molecular target for glioma treatment.

背景

Y盒结合蛋白1（YB-1）在多种癌症中异常表达。然而，YB-1在胶质瘤中的生物学功能作用尚不清楚。

方法

通过实时PCR分析MDM2和YB-1的表达。分别通过转染pcDNA-YB-1和针对YB-1的siRNA在胶质瘤细胞中过表达和敲低YB-1。通过CCK8测定法检测细胞活力。

结果

我们的研究结果表明，在54例胶质瘤患者中，胶质瘤组织中YB-1的表达高于无癌组织，且与小鼠MDM2表达呈正相关。YB-1或MDM2的过表达使暴露于替莫唑胺（TMZ）的胶质瘤细胞具有耐药特性，通过直接靶向p53。对MDM2进行基因或化学抑制可显著阻断YB-1调节的胶质瘤细胞对TMZ的反应。此外，抑制YB-1或MDM2可降低胶质瘤细胞在小鼠体内的转移和死亡率。