miR-4317 suppresses non-small cell lung cancer (NSCLC) by targeting fibroblast growth factor 9 (FGF9) and cyclin D2 (CCND2).
miR-4317 suppresses non-small cell lung cancer (NSCLC) by targeting fibroblast growth factor 9 (FGF9) and cyclin D2 (CCND2).
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DOI：
10.1186/s13046-018-0882-4
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发表时间：
2018-09-18
期刊：
影响因子：
--
通讯作者：
Sun GG
中科院分区：
文献类型：
--
作者：
He X;Chen SY;Yang Z;Zhang J;Wang W;Liu MY;Niu Y;Wei XM;Li HM;Hu WN;Sun GG
非小细胞肺癌(NSCLC)是世界范围内主要的死亡原因。MicroRNAs(MiRNAs)已被认为是癌症生物学中的关键因子。越来越多的证据表明miRNAs可作为非小细胞肺癌的诊断和预后标志物。本研究的目的是鉴定新的生物标记物miR-4317及其在非小细胞肺癌中的靶点。用原位杂交(ISH)和定量逆转录聚合酶链式反应(qRT-PCR)检测miR-4317的表达。用四甲基偶氮唑盐(3–4，5-dimethylthiazol-2-yl-5-3–carboxymethoxyphenyl-2-4-sulfophenyl-2H-tetrazolium，MTS)和集落形成实验检测细胞增殖活性，用Transwell实验检测细胞迁移和侵袭能力。用定量逆转录聚合酶链式反应和蛋白质印迹分析目的蛋白及其下游分子的表达。用双荧光素酶报告基因分析法检测miR4317基因在NSCLC细胞中的表达。我们的结果表明miR-4317在非小细胞肺癌组织和血清中表达下调，特别是在淋巴转移和临床晚期组织中。Kaplan-Meier生存分析显示，miR-4317高表达的NSCLC患者的总体生存(OS)较好。MiR-4317的高表达显著抑制了NSCLC细胞的增殖、克隆形成、迁移和侵袭，并阻碍了细胞周期。我们的结果提示miR-4317通过直接靶向成纤维细胞生长因子9(FGF9)和细胞周期蛋白D2(CCND2)发挥作用。与体外研究一致，小鼠异种移植、肺和脑转移研究证实miR-4317在体内是NSCLC的有效抑制因子miRNA。系统递送的agomiR-4317可抑制肿瘤生长，并抑制FGF9和CCND2蛋白的表达。FGF9和CCND2的重新导入减弱了miR-4317介导的对非小细胞肺癌迁移和侵袭的抑制。我们的结果表明miR-4317可以通过靶向FGF9和CCND2来减少NSCLC细胞的生长和转移。这些发现为miR-4317作为NSCLC潜在的非侵入性生物标志物和治疗靶点提供了新的证据。本文的在线版本(10.1186/s130460180882-4)包含补充材料，可供授权用户使用。
Non-small cell lung cancer (NSCLC) is a leading cause of death worldwide. MicroRNAs (miRNAs) have been indicated as crucial actors in cancer biology. Accumulating evidence suggests that miRNAs can be used as diagnostic and prognostic markers for NSCLC. The purpose of this study was to characterize and identify the novel biomarker miR-4317 and its targets in NSCLC. The expression of miR-4317 was analyzed by in situ hybridization (ISH) and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The effect of miR-4317 on proliferation was evaluated through 3–4,5-dimethylthiazol-2-yl-5-3–carboxymethoxyphenyl-2-4-sulfophenyl-2H-tetrazolium (MTS) and colony formation assays, and cell migration and invasion were evaluated through transwell assays. The expression of target proteins and downstream molecules was analyzed by qRT-PCR and western blot. Dual-luciferase reporter assay was used to assess the target genes of miR4317 in NSCLC cells. Our results demonstrated that miR-4317 was downregulated in NSCLC tissues and serum, particularly in lymph node metastasis and advanced clinical stage tissues. Kaplan-Meier survival analysis showed that NSCLC patients with high expression of miR-4317 exhibited better overall survival (OS). Enhanced expression of miR-4317 significantly inhibited proliferation, colony formation, migration and invasion, and hampered cycles of NSCLC cell lines in vitro. Our results suggested that miR-4317 functions by directly targeting fibroblast growth factor 9 (FGF9) and cyclin D2 (CCND2). In concordance with in vitro studies, mouse xenograft, lung, and brain metastatic studies validated that miR-4317 functions as a potent suppressor miRNA of NSCLC in vivo. Systemically delivered agomiR-4317 reduced tumor growth and inhibited FGF9 and CCND2 protein expression. Reintroduction of FGF9 and CCND2 attenuated miR-4317-mediated suppression of migration and invasion in NSCLC. Our results indicate that miR-4317 can reduce NSCLC cell growth and metastasis by targeting FGF9 and CCND2. These findings provide new evidence of miR-4317 as a potential non-invasive biomarker and therapeutic target for NSCLC. The online version of this article (10.1186/s13046-018-0882-4) contains supplementary material, which is available to authorized users.
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