Long noncoding RNA RP11-838N2.4 enhances the cytotoxic effects of temozolomide by inhibiting the functions of miR-10a in glioblastoma cell lines.
Long noncoding RNA RP11-838N2.4 enhances the cytotoxic effects of temozolomide by inhibiting the functions of miR-10a in glioblastoma cell lines.
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DOI：
10.18632/oncotarget.9699
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发表时间：
2016-07-12
期刊：
影响因子：
--
通讯作者：
Guo H
中科院分区：
文献类型：
--
作者：
Liu Y;Xu N;Liu B;Huang Y;Zeng H;Yang Z;He Z;Guo H
替莫唑胺（temolozomide，TMZ）是治疗胶质母细胞瘤（glioblastomas，GBM）的标准化疗药物，其耐药性是GBM患者的主要临床问题。最近，长链非编码RNA（lncRNA）已被牵连在各种癌症的化疗耐药性。在这项研究中，我们发现与亲本非抗性GBM细胞（U87，U251）相比，TMZ抗性GBM细胞（U87 TR，U251 TR）中lncRNA RP 11 - 838 N2.4的水平较低。在GBM患者中，lncRNA RP 11 - 838 N2.4水平的降低与GBM复发的风险较高以及术后生存时间较短相关。我们进一步发现lncRNA RP 11 -838N2.4可以增强替莫唑胺在体内和体外对GBM细胞的细胞毒性作用。此外，lncRNA RP 11 - 838 N2.4作为内源性海绵，通过保守序列抑制miR-10a的功能，并增加EphA 8的表达，从而增强细胞凋亡率，从而增强GBM细胞对TMZ的敏感性。此外，lncRNA RP 11 -838N2.4不依赖于miR-10a而抑制转化生长因子-β（TGF-β）的活性。最后，lncRNA RP 11 -838N2.4的表征可能有助于增强TMZ功效的策略。
Resistance to temolozomide (TMZ), the standard chemotherapy agent for treating glioblastomas (GBM), is a major clinical problem for patients with GBM. Recently, long noncoding RNAs (lncRNAs) have been implicated in chemotherapy resistance in various cancers. In this study, we found that the level of the lncRNA RP11-838N2.4 was lower in TMZ-resistant GBM cells (U87TR, U251TR) compared to the parental, non-resistant GBM cells (U87, U251). In GBM patients, the decreased level of lncRNA RP11-838N2.4 correlated with higher risk of GBM relapse, as well as shorter postoperative survival times. We further found that lncRNA RP11-838N2.4 could enhances the cytotoxic effects of temozolomide to GBM cells both in vivo and in vitro. Moreover, lncRNA RP11-838N2.4 acts as an endogenous sponge, suppressing the function of miR-10a through conserved sequences and increasing the expression of EphA8 that enhanced the rate of cell apoptosis, thereby intensified sensitivity of GBM cells to TMZ. Additionally, lncRNA RP11-838N2.4 inhibited the activity of transforming growth factor-β (TGF-β) independent of miR-10a. Finally, Characterization of lncRNA RP11-838N2.4 could contribute to strategies for enhancing the efficacy of TMZ.
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作者：
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