miR-223 functions as a potent tumor suppressor of the Lewis lung carcinoma cell line by targeting insulin-like growth factor-1 receptor and cyclin-dependent kinase 2.
miR-223 functions as a potent tumor suppressor of the Lewis lung carcinoma cell line by targeting insulin-like growth factor-1 receptor and cyclin-dependent kinase 2.
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DOI：
10.3892/ol.2013.1375
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发表时间：
2013-08
期刊：
影响因子：
2.9
通讯作者：
Wang D
中科院分区：
文献类型：
--
作者：
Nian W;Ao X;Wu Y;Huang Y;Shao J;Wang Y;Chen Z;Chen F;Wang D
microRNA（miRNAs）被认为是癌基因或肿瘤抑制基因，通过靶向特定的肿瘤相关基因发挥作用。先前的研究已经报道了miR-223可能在许多癌症类型中作为肿瘤抑制因子，然而，关于其在非小细胞肺癌（NSCLC）中的靶点的知识仍然有限。在本研究中，通过CCK-8测定、生长曲线和刘易斯肺癌（LLC）细胞系中的锚定非依赖性生长测定，发现miR-223在体外抑制细胞增殖。在LLC细胞中观察到miR-223转染显著抑制迁移和侵袭，诱导G2/M期阻滞，并降低小鼠干细胞标志物Sca-1的表达水平。此外，miR-223转染显著抑制AKT和ERK信号传导，以及胰岛素样生长因子-1受体（IGF-1 R）介导的下游信号传导，这些信号传导途径对NSCLC细胞的细胞增殖和侵袭至关重要。在C57 BL/6小鼠中的分析表明，miR-223抑制体内致瘤性。使用荧光素酶活性测定和蛋白质印迹分析，IGF-1 R和细胞周期蛋白依赖性激酶2（CDK 2）被鉴定为miR-223的直接靶点。在本研究中，在LLC细胞系中鉴定并验证了miR-223的新癌症相关靶点，表明miR-223作为肿瘤抑制因子发挥作用，可能微调肺癌中IGF-1 R途径的活性。因此，增加miR-223的表达可能为NSCLC的治疗提供新的方法。
microRNAs (miRNAs) have been hypothesized to function as oncogenes or tumor suppressors by targeting specific cancer-related genes. Previous studies have reported that miR-223 may serve as a tumor suppressor in a number of cancer types, however, knowledge of its targets in non-small cell lung cancer (NSCLC) remains limited. In the current study, miR-223 was found to inhibit cell proliferation in vitro by CCK-8 assay, growth curves and an anchorage-independent growth assay in a Lewis lung carcinoma (LLC) cell line. miR-223 transfection in the LLC cells was observed to significantly inhibit migration and invasion, induce G2/M arrest and decrease the expression levels of Sca-1, a marker of murine stem cells. In addition, miR-223 transfection markedly suppressed AKT and ERK signaling, as well as insulin-like growth factor-1 receptor (IGF-1R)-mediated downstream signaling, pathways that are crucial for cell proliferation and invasion in NSCLC cells. Analyses in C57BL/6 mice demonstrated that miR-223 suppresses tumorigenicity in vivo. Using a luciferase activity assay and western blot analysis, IGF-1R and cyclin-dependent kinase 2 (CDK2) were identified as direct targets of miR-223. In the present study, novel cancer-related targets of miR-223 were identified and verified in a LLC cell line, indicating that miR-223 functions as a tumor suppressor, which may fine-tune the activity of the IGF-1R pathway in lung cancer. Therefore, increasing miR-223 expression may provide a novel approach for the treatment of NSCLC.
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