miR-519a enhances chemosensitivity and promotes autophagy in glioblastoma by targeting STAT3/Bcl2 signaling pathway.
miR-519a enhances chemosensitivity and promotes autophagy in glioblastoma by targeting STAT3/Bcl2 signaling pathway.
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miR-519a通过靶向STAT3/Bcl2信号通路增强胶质母细胞瘤的化疗敏感性并促进自噬
DOI：
10.1186/s13045-018-0618-0
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发表时间：
2018-05-29
影响因子：
28.5
通讯作者：
Lu YT
中科院分区：
文献类型：
--
作者：
Li H;Chen L;Li JJ;Zhou Q;Huang A;Liu WW;Wang K;Gao L;Qi ST;Lu YT
背景：替莫唑胺（TMZ）的耐药性是胶质母细胞瘤（GBM）治疗的主要挑战。我们先前发现miR-519 a通过靶向信号转导和转录激活因子3（STAT 3）介导的自噬致癌途径在胶质瘤中发挥肿瘤抑制剂的作用。在这里，我们研究了miR-519 a对GBM细胞中TMZ化疗敏感性和自噬的影响。此外，潜在的分子机制和信号通路进行了explored.Methods：在本研究中，两个稳定的TMZ耐药GBM细胞系成功地通过暴露的亲本细胞逐渐增加TMZ浓度。用miR-519 a模拟物或抑制剂分别转染U87-MG/TMZ和U87-MG细胞后，通过MTT、细胞凋亡和集落形成等一系列生化检测来确定TMZ对U87-MG/TMZ的化疗敏感性。应用透射电镜、LC 3B蛋白免疫荧光和Western blotting检测GBM细胞自噬水平。使用慢病毒建立了GBM细胞中miR-519 a的稳定敲低和过表达。使用异种移植裸鼠模型和原位脑模型来检查miR-519 a的体内作用。结果：TMZ处理后U87-MG细胞中miR-519 a表达显著上调，而U87-MG/TMZ细胞中miR-519 a表达无明显上调。此外，与U87-MG细胞相比，U87-MG/TMZ细胞中miR-519 a的表达和基线自噬水平较低。miR-519 a显著增强U87-MG/TMZ细胞中TMZ诱导的自噬和凋亡性细胞死亡，而抑制miR-519 a促进U87-MG细胞中TMZ抗性并减少TMZ诱导的自噬。此外，miR-519 a通过修饰STAT 3表达诱导自噬。体内实验结果表明，miR-519 a可以通过促进自噬和靶向STAT 3/Bcl-2/Beclin-1通路来增强细胞凋亡并使GBM对TMZ治疗敏感。在人GBM组织中，我们发现miR-519 a和STAT 3表达之间呈负相关。结论：我们的结果表明，miR-519 a增加GBM细胞对TMZ治疗的敏感性。miR-519 a的积极作用可能通过自噬介导。此外，miR-519 a过表达可通过抑制STAT 3/Bcl-2通路诱导自噬。因此，miR-519 a和TMZ的组合可能代表GBM中的有效治疗策略。
Background:Chemoresistance to temozolomide (TMZ) is a major challenge in the treatment of glioblastoma (GBM). We previously found that miR-519a functions as a tumor suppressor in glioma by targeting the signal transducer and activator of transcription 3 (STAT3)-mediated autophagy oncogenic pathway. Here, we investigated the effects of miR-519a on TMZ chemosensitivity and autophagy in GBM cells. Furthermore, the underlying molecular mechanisms and signaling pathways were explored.Methods:In the present study, two stable TMZ-resistant GBM cell lines were successfully generated by exposure of parental cells to a gradually increasing TMZ concentration. After transfecting U87-MG/TMZ and U87-MG cells with miR-519a mimic or inhibitor, a series of biochemical assays such as MTT, apoptosis, and colony formation were performed to determine the chemosensitive response to TMZ. The autophagy levels in GBM cells were detected by transmission electron microscopy, LC3B protein immunofluorescence, and Western blotting analysis. Stable knockdown and overexpression of miR-519a in GBM cells were established using lentivirus. A xenograft nude mouse model and in situ brain model were used to examine the in vivo effects of miR-519a. Tumor tissue samples were collected from 48 patients with GBM and were used to assess the relationship between miR-519a and STAT3 expression.Results:TMZ treatment significantly upregulated miR-519a in U87-MG cells but not in U87-MG/TMZ cells. Moreover, the expression of miR-519a and baseline autophagy levels was lower in U87-MG/TMZ cells as compared to U87-MG cells. miR-519a dramatically enhanced TMZ-induced autophagy and apoptotic cell death in U87-MG/TMZ cells, while inhibition of miR-519a promoted TMZ resistance and reduced TMZ-induced autophagy in U87-MG cells. Furthermore, miR-519a induced autophagy through modification of STAT3 expression. The in vivo results showed that miR-519a can enhance apoptosis and sensitized GBM to TMZ treatment by promoting autophagy and targeting the STAT3/Bcl-2/Beclin-1 pathway. In human GBM tissues, we found an inverse correlation between miR-519a and STAT3 expression.Conclusions:Our results suggested that miR-519a increased the sensitivity of GBM cells to TMZ therapy. The positive effects of miR-519a may be mediated through autophagy. In addition, miR-519a overexpression can induce autophagy by inhibiting STAT3/Bcl-2 pathway. Therefore, a combination of miR-519a and TMZ may represent an effective therapeutic strategy in GBM.
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影响因子：
11.2
作者：
Hu YL;DeLay M;Jahangiri A;Molinaro AM;Rose SD;Carbonell WS;Aghi MK
通讯作者：
Aghi MK
影响因子：
11.1
作者：
He C;Klionsky DJ
通讯作者：
Klionsky DJ
影响因子：
3.7
作者：
Lin CJ;Lee CC;Shih YL;Lin CH;Wang SH;Chen TH;Shih CM
通讯作者：
Shih CM
二甲双胍通过下调 Stat3 信号促进食管鳞状细胞癌自噬和凋亡
影响因子：
9
作者：
通讯作者：
--
影响因子：
28.5
作者：
Gravina GL;Mancini A;Marampon F;Colapietro A;Delle Monache S;Sferra R;Vitale F;Richardson PJ;Patient L;Burbidge S;Festuccia C
通讯作者：
Festuccia C