MiR-488 inhibits proliferation and cisplatin sensibility in non-small-cell lung cancer (NSCLC) cells by activating the eIF3a-mediated NER signaling pathway.
MiR-488 inhibits proliferation and cisplatin sensibility in non-small-cell lung cancer (NSCLC) cells by activating the eIF3a-mediated NER signaling pathway.
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MiR-488 通过激活 eIF3a 介导的 NER 信号通路抑制非小细胞肺癌 (NSCLC) 细胞的增殖和顺铂敏感性
DOI：
10.1038/srep40384
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发表时间：
2017-01-11
影响因子：
4.6
通讯作者：
Liu ZQ
中科院分区：
文献类型：
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作者：
Fang C;Chen YX;Wu NY;Yin JY;Li XP;Huang HS;Zhang W;Zhou HH;Liu ZQ
我们前期的研究表明，真核生物翻译起始因子3a（eIF 3a）可增加肺癌铂类化疗的敏感性。miRNAs在肺癌的发生和药物反应中起重要作用。在这项研究中，我们的目的是确定潜在的内源性miRNAs抑制eIF 3a的表达，并确定他们的影响，这种抑制顺铂耐药。通过生物信息学分析预测和双荧光素酶报告基因检测证实，我们发现miRNA-488通过直接与eIF 3a的3 'UTR结合来抑制eIF 3a的表达。此外，miRNA-488的过表达抑制了A549细胞的迁移和侵袭能力，并通过上调P27的表达抑制了细胞增殖和细胞周期进程。与亲本细胞系相比，A549/顺铂（DDP）抗性细胞表现出更高水平的miRNA-488。此外，我们发现miRNA-488与三种非小细胞肺癌细胞（A549、H1299和SK-MES-1）的顺铂耐药性相关。miRNA-488诱导顺铂耐药的机制是通过增加复制蛋白A（RPA）14和着色性干皮病C组（XPC）的表达激活核苷酸切除修复（NER）。总之，我们的结果表明，miRNA-488是一种肿瘤抑制miRNA，通过靶向eIF 3a发挥作用。此外，miRNA-488还参与eIF 3a介导的NSCLC细胞顺铂耐药。
Our previous studied indicated that eukaryotic translation initiation factor 3a (eIF3a) increases the sensitive of platinum-based chemotherapy in lung cancer. MiRNAs play an important role in lung carcinogenesis and drug response. In this study, we aimed to identify potential endogenous miRNAs that inhibit eIF3a expression and determine their influence of this inhibition on cisplatin resistance. Using bioinformatics analysis prediction and confirmation with dual-luciferase reporter assays, we found that miRNA-488 inhibited eIF3a expression by directly binding to the 3’UTR of eIF3a. In addition, the overexpression of miRNA-488 inhibited cell migration and invasion in A549 cells, and also inhibited cell proliferation, cell cycle progression by elevated P27 expression. Compared to the parental cell line, A549/cisplatin (DDP) resistant cells exhibited a higher level of miRNA-488. Moreover, we found that miRNA-488 was associated with cisplatin resistance in three NSCLC cells (A549, H1299 and SK-MES-1). The mechanism of miRNA-488 induced cisplatin resistance was that miRNA-488 activated nucleotide excision repair (NER) by increasing the expression of Replication Protein A (RPA) 14 and Xeroderma pigmentosum group C (XPC). In conclusion, our results demonstrated that miRNA-488 is a tumor suppressor miRNA that acts by targeting eIF3a. Moreover, miRNA-488 also participates in eIF3a mediated cisplatin resistance in NSCLC cells.