Su Jiancheng, Ruan Shaolin, Dai Shengkun, Mi Jing, Chen Wei, Jiang Songshan
Department of Biological Sciences & Technology, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China.
Department of Gynecology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China.
Pharmacogenomics. 2019 Feb;20(3):155-165. doi: 10.2217/pgs-2018-0161. Epub 2018 Dec 13.
NF1 loss confers chemoresistance in multiple cancers. However, the etiology remains largely unknown. Our study aimed to scrutinize the role of NF1 in chemoresistant ovarian cancer and its underlying mechanism.
MATERIALS & METHODS: 4',6-diamidino-2-phenylindole staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, luciferase reporter assay, chromatin immunoprecipitation, Western blot, quantitative real-time-PCR and rescue experiments were performed to illustrate the antiapoptotic role of NF1 loss and its underlying mechanism.
NF1-knockdown ovarian cells showed resistance to cisplatin-induced apoptosis. Furthermore, NF1 regulated MCL1 expression at protein level. Further dissections suggested that miR-142-5p was regulated by NF1 via its promoter and targeted MCL1. Consistently, miR-142-5p mimic and si-MCL1 can attenuate the antiapoptotic effect of NF1 knockdown.
NF1 knockdown endowed ovarian cells with resistance to cisplatin-induced apoptosis by targeting MCL1 via miR-142-5p.
神经纤维瘤病1型（NF1）缺失在多种癌症中赋予化疗耐药性。然而，其病因在很大程度上仍不清楚。我们的研究旨在探究NF1在化疗耐药性卵巢癌中的作用及其潜在机制。
进行4',6-二脒基-2-苯基吲哚染色、末端脱氧核苷酸转移酶介导的dUTP缺口末端标记检测、荧光素酶报告基因检测、染色质免疫沉淀、蛋白质免疫印迹、定量实时聚合酶链反应及挽救实验，以阐明NF1缺失的抗凋亡作用及其潜在机制。
NF1基因敲低的卵巢癌细胞对顺铂诱导的凋亡具有抗性。此外，NF1在蛋白质水平上调节髓细胞白血病序列1（MCL1）的表达。进一步分析表明，微小RNA-142-5p（miR-142-5p）由NF1通过其启动子进行调控，并靶向MCL1。一致地，miR-142-5p模拟物和MCL1小干扰RNA（si-MCL1）可减弱NF1基因敲低的抗凋亡作用。
NF1基因敲低通过miR-142-5p靶向MCL1，赋予卵巢细胞对顺铂诱导凋亡的抗性。
