LncRNA NEAT1 contributes to paclitaxel resistance of ovarian cancer cells by regulating ZEB1 expression via miR-194.
LncRNA NEAT1 contributes to paclitaxel resistance of ovarian cancer cells by regulating ZEB1 expression via miR-194.
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DOI：
10.2147/ott.s147586
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发表时间：
2017
影响因子：
4
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
An J;Lv W;Zhang Y
化疗耐药是临床肿瘤治疗的主要障碍之一。核旁斑组装转录本1(NEAT1)是肺癌、食道癌、胃癌等多种恶性肿瘤的致癌基因。本研究旨在探讨NEAT1在卵巢癌紫杉醇耐药中的作用及其可能的分子机制。用实时定量聚合酶链式反应(qRT-PCR)检测NEAT1和miR-194在卵巢癌组织和细胞中的表达。采用四甲基偶氮唑盐比色法、流式细胞仪和Western印迹法检测NEAT1对耐药卵巢癌细胞PTX耐药性的影响。用荧光素酶报告法检测NEAT1、锌指E盒结合同源框1(ZEB1)和miR-194之间的关系。建立卵巢癌移植瘤模型，证实NEAT1在卵巢癌PTX耐药中的生物学作用。在对PTX耐药的卵巢癌组织和细胞中，NEAT1上调，miR-194下调。在功能上，NEAT1基因敲除通过在体外促进PTX诱导的细胞凋亡来增强细胞对PTX的敏感性。NEAT1被鉴定为miR-194上调ZEB1表达的分子海绵。从机制上讲，NEAT1基因敲除诱导的PTX敏感性是通过miR-194/ZEB1轴介导的。此外，NEAT1基因敲除提高了卵巢癌体内PTX的敏感性。NEAT1通过诱导miR-194上调ZEB1的表达，阐明了耐药卵巢癌细胞化疗耐药的新调控途径，为卵巢癌的靶向治疗提供了一种可能的长非编码RNA(LncRNA)靶向治疗。
Chemoresistance is one of the major obstacles for cancer therapy in the clinic. Nuclear paraspeckle assembly transcript 1 (NEAT1) has been reported as an oncogene in most malignancies such as lung cancer, esophageal cancer, and gastric cancer. This study is designed to investigate the function of NEAT1 in paclitaxel (PTX) resistance of ovarian cancer and its potential molecular mechanism. The expressions of NEAT1 and miR-194 in ovarian cancer tissues and cells were estimated by quantitative real-time polymerase chain reaction (qRT-PCR). MTT, flow cytometry, and Western blot assays were used to assess the effect of NEAT1 on PTX resistance in PTX-resistant ovarian cancer cells. Luciferase reporter assay was applied to examine the association between NEAT1, zinc finger E-box-binding homeobox 1 (ZEB1) and miR-194. Xenograft tumor model was established to confirm the biological role of NEAT1 in PTX resistance of ovarian cancer in vivo. NEAT1 was upregulated, and miR-194 was downregulated in PTX-resistant ovarian cancer tissues and cells. Functionally, NEAT1 knockdown enhanced cell sensitivity to PTX via promoting PTX-induced apoptosis in vitro. NEAT1 was identified as a molecular sponge of miR-194 to upregulate ZEB1 expression. Mechanistically, NEAT1-knockdown-induced PTX sensitivity was mediated by miR-194/ZEB1 axis. Moreover, NEAT1 knockdown improved PTX sensitivity of ovarian cancer in vivo. NEAT1 contributed to PTX resistance of ovarian cancer cells at least partly through upregulating ZEB1 expression by sponging miR-194, elucidating a novel regulatory pathway of chemoresistance in PTX-resistant ovarian cancer cells and providing a possible long noncoding RNA (lncRNA)-targeted therapy for ovarian cancer.