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MicroRNA-30a targets BECLIN-1 to inactivate autophagy and sensitizes gastrointestinal stromal tumor cells to imatinib
Cell Death & Disease ( IF 8.1 ) Pub Date : 2020-03-23 , DOI: 10.1038/s41419-020-2390-7
Wei Chen 1, 2 , Zhouqi Li 3 , Hao Liu 1, 2 , Sujing Jiang 4 , Guannan Wang 3 , Lifeng Sun 5 , Jun Li 5 , Xiaochen Wang 5 , Shaojun Yu 5 , Jianjin Huang 3 , Ying Dong 3
Affiliation  

Gastrointestinal stromal tumors (GISTs), the most widespread type of sarcoma, contain driver gene mutations predominantly of receptor tyrosine kinase and platelet-derived growth factor receptor alpha. However, the inevitable development of resistance to imatinib (IM) cannot be fully attributed to secondary driver gene mutations. In this study, we investigated the role of microRNA-30a in sensitization of GIST cells to IM in vivo and in vitro. Higher levels of miR-30a were detected in GIST-T1 cells, which were more sensitive to IM than GIST-882 cells. IM treatment also reduced miR-30a levels, indicating the possible role of miR-30a in GIST IM resistance. Subsequently, miR-30a was confirmed to be an IM sensitizer via a mechanism that was attributed to its involvement in the regulation of cell autophagy. The interaction of miR-30a and autophagy in IM treated GIST cells was found to be linked by beclin-1. Beclin-1 knockdown increased IM sensitivity in GIST cell lines. Finally, miR-30a was confirmed to enhance IM sensitivity of GIST cells in mouse tumor models. Our study provides evidence for the possible role of miR-30a in the emergence of secondary IM resistance in GIST patients, indicating a promising target for overcoming this chemoresistance.



中文翻译:

MicroRNA-30a靶向BECLIN-1以使自噬失活并使胃肠道间质肿瘤细胞对伊马替尼敏感

胃肠道间质瘤(GIST)是肉瘤最广泛的类型,其驱动基因突变主要是受体酪氨酸激酶和血小板源性生长因子受体α。但是,对伊马替尼(IM)耐药性的必然发展不能完全归因于继发性驱动基因突变。在这项研究中,我们研究了microRNA-30a在体内和体外GIST细胞对IM致敏中的作用。在GIST-T1细胞中检测到更高水平的miR-30a,它对IM的敏感性高于GIST-882细胞。IM治疗还降低了miR-30a的水平,表明miR-30a在GIST IM抵抗中的可能作用。随后,通过归因于其参与细胞自噬调节的机制,证实miR-30a是IM敏化剂。发现miR-30a和自噬在经IM处理的GIST细胞中的相互作用与beclin-1相关。Beclin-1敲低可提高GIST细胞系的IM敏感性。最后,证实miR-30a可增强小鼠肿瘤模型中GIST细胞的IM敏感性。我们的研究提供了miR-30a在GIST患者继发IM抵抗中可能发挥作用的证据,表明了克服这种化学耐药性的有希望的靶标。

更新日期:2020-03-24
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