Regulation of TPD52 by antitumor microRNA-218 suppresses cancer cell migration and invasion in lung squamous cell carcinoma.
Regulation of TPD52 by antitumor microRNA-218 suppresses cancer cell migration and invasion in lung squamous cell carcinoma.
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DOI：
10.3892/ijo.2016.3690
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发表时间：
2016-11
影响因子：
5.2
通讯作者：
Inoue H
中科院分区：
文献类型：
--
作者：
Kumamoto T;Seki N;Mataki H;Mizuno K;Kamikawaji K;Samukawa T;Koshizuka K;Goto Y;Inoue H
靶向分子治疗的发展使肺腺癌患者受益匪浅。相比之下，这些治疗在肺鳞状细胞癌（肺SCC）的管理中几乎没有益处。因此，肺SCC需要基于当前基因组方法的新治疗选择。已显示异常microRNA（miRNA）表达促进肺癌发展和侵袭性。在我们的癌症的miRNA表达特征中经常观察到microRNA-218（miR-218）的下调，并且先前的研究已经显示了miR-218在几种类型的癌症中的抗肿瘤功能。然而，miR-218对肺SCC的影响仍然不明确。本研究探讨了miR-218在肺鳞癌中的抗肿瘤作用，以确定该miRNA调控的靶基因。miR-218的异位表达极大地抑制了肺SCC细胞系EBC-1和SK-MES-1中癌细胞的迁移和侵袭。通过计算机分析和基因表达数据搜索的组合，选择肿瘤蛋白D52（TPD 52）作为miR-218调控的推定靶点。双荧光素酶报告基因检测显示，miR-218与TPD 52的3′-UTR直接结合。在肺SCC临床标本中观察到TPD 52的过表达，并且TPD 52的敲低显著抑制肺SCC细胞系中的癌细胞迁移和侵袭。此外，由TPD 52介导的下游途径涉及基因组稳定性和有丝分裂检查点基因的关键调节因子。综上所述，我们的数据表明，下调miR-218增强了肺SCC细胞中TPD 52的过表达，促进了癌细胞的侵袭性。肺SCC中肿瘤抑制性miRNA介导的RNA网络的鉴定将为该疾病分子发病机制的潜在机制提供新的见解。
The development of targeted molecular therapies has greatly benefited patients with lung adenocarcinomas. In contrast, these treatments have had little benefit in the management of lung squamous cell carcinoma (lung SCC). Therefore, new treatment options based on current genomic approaches are needed for lung SCC. Aberrant microRNA (miRNA) expression has been shown to promote lung cancer development and aggressiveness. Downregulation of microRNA-218 (miR-218) was frequently observed in our miRNA expression signatures of cancers, and previous studies have shown an antitumor function of miR-218 in several types of cancers. However, the impact of miR-218 on lung SCC is still ambiguous. The present study investigated the antitumor roles of miR-218 in lung SCC to identify the target genes regulated by this miRNA. Ectopic expression of miR-218 greatly inhibited cancer cell migration and invasion in the lung SCC cell lines EBC-1 and SK-MES-1. Through a combination of in silico analysis and gene expression data searching, tumor protein D52 (TPD52) was selected as a putative target of miR-218 regulation. Moreover, direct binding of miR-218 to the 3′-UTR of TPD52 was observed by dual luciferase reporter assay. Overexpression of TPD52 was observed in lung SCC clinical specimens, and knockdown of TPD52 significantly suppressed cancer cell migration and invasion in lung SCC cell lines. Furthermore, the downstream pathways mediated by TPD52 involved critical regulators of genomic stability and mitotic checkpoint genes. Taken together, our data showed that downregulation of miR-218 enhances overexpression of TPD52 in lung SCC cells, promoting cancer cell aggressiveness. Identification of tumor-suppressive miRNA-mediated RNA networks of lung SCC will provide new insights into the potential mechanisms of the molecular pathogenesis of the disease.
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