Long noncoding RNA AC003092.1 promotes temozolomide chemosensitivity through miR-195/TFPI-2 signaling modulation in glioblastoma.
Long noncoding RNA AC003092.1 promotes temozolomide chemosensitivity through miR-195/TFPI-2 signaling modulation in glioblastoma.
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长非编码RNA AC003092.1通过miR-195/TFPI-2信号调节在胶质母细胞瘤中促进替莫唑胺化疗敏感性
DOI：
10.1038/s41419-018-1183-8
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发表时间：
2018-11-15
影响因子：
9
通讯作者：
Guo H
中科院分区：
文献类型：
--
作者：
Xu N;Liu B;Lian C;Doycheva DM;Fu Z;Liu Y;Zhou J;He Z;Yang Z;Huang Q;Zeng H;Guo H
替莫唑胺（TMZ）联合放射治疗被认为是胶质母细胞瘤（GB）患者手术后最有效的治疗方法。然而，由于对TMZ的内在或发展中的耐药性，总体临床预后仍然不令人满意。近年来，越来越多的证据表明，长链非编码RNA（lncRNA）在肿瘤的各种生物学过程中起着关键作用，并与多种药物的耐药性有关。然而，lncRNA在TMZ抗性中的作用知之甚少。在此，我们发现lncRNA AC003092.1的表达在TMZ抗性（TR）的GB细胞（U87 TR和U251 TR）中与其亲本细胞（U87和U251）相比显著降低。在胶质瘤患者中，低水平的lncRNA AC003092.1与TMZ耐药性增加、复发风险较高和预后不良相关。lncRNA AC003092.1的过表达增强TMZ敏感性，促进细胞凋亡，并抑制TMZ耐药GB细胞的细胞增殖。此外，我们确定lncRNA AC003092.1通过TFPI-2介导的细胞凋亡在体外和体内调节TMZ化疗敏感性。进一步的研究表明，lncRNA AC003092.1通过miR-195调节GB中TFPI-2的表达。总之，这些数据表明，lncRNA AC003092.1可以通过充当内源性CeRNA来抑制miR-195的功能，导致TFPI-2的表达增加;这促进TMZ诱导的细胞凋亡，从而使GB细胞对TMZ更敏感。我们的研究结果表明，lncRNA AC003092.1的过表达可能是一种潜在的治疗，以克服TMZ耐药的GB患者。
Temozolomide (TMZ) and radiation therapy combination for glioblastoma (GB) patients has been considered as the most effective therapy after surgical procedure. However, the overall clinical prognosis remains unsatisfactory due to intrinsic or developing resistance to TMZ. Recently, increasing evidence suggested that long noncoding RNAs (lncRNAs) play a critical role in various biological processes of tumors, and have been implicated in resistance to various drugs. However, the role of lncRNAs in TMZ resistance is poorly understood. Here, we found that the expression of lncRNA AC003092.1 was markedly decreased in TMZ resistance (TR) of GB cells (U87TR and U251TR) compared with their parental cells (U87 and U251). In patients with glioma, low levels of lncRNA AC003092.1 were correlated with increased TMZ resistance, higher risk of relapse, and poor prognosis. Overexpression of lncRNA AC003092.1 enhances TMZ sensitivity, facilitates cell apoptosis, and inhibits cell proliferation in TMZ-resistant GB cells. In addition, we identified that lncRNA AC003092.1 regulates TMZ chemosensitivity through TFPI-2-mediated cell apoptosis in vitro and in vivo. Mechanistically, further investigation revealed that lncRNA AC003092.1 regulates TFPI-2 expression through miR-195 in GB. Taken together, these data suggest that lncRNA AC003092.1 could inhibit the function of miR-195 by acting as an endogenous CeRNA, leading to increased expression of TFPI-2; this promotes TMZ-induced apoptosis, thereby making GB cells more sensitive to TMZ. Our findings indicate that overexpression of lncRNA AC003092.1 may be a potential therapy to overcome TMZ resistance in GB patients.
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影响因子：
9
作者：
Bao X;Ren T;Huang Y;Sun K;Wang S;Liu K;Zheng B;Guo W
通讯作者：
Guo W
影响因子：
3.7
作者：
Liu H;Wang G;Yang L;Qu J;Yang Z;Zhou X
通讯作者：
Zhou X
影响因子：
8.4
作者：
Bai, Yifeng;Liao, Hongzhan;Guo, Linlang
通讯作者：
Guo, Linlang
影响因子：
9.7
作者：
Munoz, Jessian L.;Walker, Nykia D.;Rameshwar, Pranela
通讯作者：
Rameshwar, Pranela
影响因子：
4
作者：
Cai T;Liu Y;Xiao J
通讯作者：
Xiao J