Chen Jing, Liu Xiaobei, Xu Yichen, Zhang Kai, Huang Jiayuan, Pan Banzhou, Chen Dongqin, Cui Shiyun, Song Haizhu, Wang Rui, Chu Xiaoyuan, Zhu Xiaoli, Chen Longbang
Department of Respiratory, Zhongda Hospital, Southeast University, Nanjing, China; Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, China.
Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, China.
Mol Ther Nucleic Acids. 2019 Mar 1;14:567-582. doi: 10.1016/j.omtn.2019.01.005. Epub 2019 Jan 18.
Chemoresistance remains a great obstacle in effective lung adenocarcinoma (LUAD) treatment. Previously, we verified the role of microRNA-200b (miR-200b) in the formation of docetaxel (DTX)-resistant LUAD cells. This study aims to investigate the mechanism underlying the low level of miR-200b in DTX-resistant LUAD cells. The real-time reverse transcription (RT) lncRNA PCR array system was applied to explore lncRNAs that potentially regulated miR-200b in DTX-resistant LUAD cells. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) contributed to the low miR-200b level in DTX-resistant LUAD cells. Functional assays were conducted to determine the role of MALAT1 in regulating the growth and metastasis of parental and DTX-resistant LUAD cells. Investigation revealed the mechanism of the competing endogenous RNA (ceRNA) pathway. MALAT1 regulated miR-200b by acting as a ceRNA. MALAT1 modulated the sensitivity of LUAD cells to DTX. E2F transcription factor 3 (E2F3) and zinc-finger E-box binding homeobox 1 (ZEB1) were two targets of miR-200b and mediated the function of MALAT1 in DTX-resistant LUAD cells. Transcription factor AP-2 gamma (TFAP2C) and ZEB1 activated the MALAT1 transcription. In conclusion, TFAP2C-activated MALAT1 modulated the chemoresistance of LUAD cells by sponging miR-200b to upregulate E2F3 and ZEB1. Our findings may provide novel therapeutic targets and perspectives for LUAD treatment.
化疗耐药仍然是有效治疗肺腺癌（LUAD）的一大障碍。此前，我们验证了微小RNA-200b（miR-200b）在多西他赛（DTX）耐药LUAD细胞形成中的作用。本研究旨在探究DTX耐药LUAD细胞中miR-200b水平较低的潜在机制。应用实时逆转录（RT）lncRNA PCR阵列系统，探索在DTX耐药LUAD细胞中可能调控miR-200b的lncRNAs。转移相关肺腺癌转录本1（MALAT1）导致DTX耐药LUAD细胞中miR-200b水平降低。进行功能分析以确定MALAT1在调控亲本及DTX耐药LUAD细胞生长和转移中的作用。研究揭示了竞争性内源RNA（ceRNA）途径的机制。MALAT1通过作为ceRNA来调控miR-200b。MALAT1调节LUAD细胞对DTX的敏感性。E2F转录因子3（E2F3）和锌指E盒结合同源框1（ZEB1）是miR-200b的两个靶标，并介导MALAT1在DTX耐药LUAD细胞中的功能。转录因子AP-2γ（TFAP2C）和ZEB1激活MALAT1转录。总之，TFAP2C激活的MALAT1通过吸附miR-200b上调E2F3和ZEB1来调节LUAD细胞的化疗耐药性。我们的研究结果可能为LUAD治疗提供新的治疗靶点和思路。
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