Downregulation of matrix metalloproteinase 14 by the antitumor miRNA, miR-150-5p, inhibits the aggressiveness of lung squamous cell carcinoma cells
Downregulation of matrix metalloproteinase 14 by the antitumor miRNA, miR-150-5p, inhibits the aggressiveness of lung squamous cell carcinoma cells
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DOI：
10.3892/ijo.2017.4232
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发表时间：
2018-03-01
影响因子：
5.2
通讯作者：
Inoue, Hiromasa
中科院分区：
文献类型：
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作者：
Suetsugu, Takayuki;Koshizuka, Keiichi;Inoue, Hiromasa
在本研究中，为了阐明肺鳞状细胞癌（LUSQ）的侵袭性，我们研究了LUSQ细胞中由抗肿瘤microRNAs（miRNAs或miRs）调控的致癌RNA网络。我们对人类癌症的原始miRNA表达特征的分析显示，microRNA-150- 5 p（miR-150- 5 p）在各种类型的癌症中下调，表明miR-150- 5 p通过靶向几种致癌基因而作为抗肿瘤miRNA。因此，本研究的目的是研究miR-150- 5 p在LUSQ细胞中的抗肿瘤作用，并鉴定参与LUSQ侵袭行为的miR-150- 5 p调控的癌基因。在LUSQ和细胞系（SK-MES-1和EBC-1）的临床样本中验证了miR-150- 5 p的下调。miR-150- 5 p的异位过表达显著抑制癌细胞的侵袭性。综合基因表达分析显示，miR-150- 5 p在LUSQ细胞中调控9个基因。其中，基质金属蛋白酶14（MMP 14）被发现是miR-150- 5 p的直接靶点，如荧光素酶报告基因测定所示。使用针对MMP 14的siRNA敲低MMP 14（si-MMP 14）显著抑制癌细胞迁移和侵袭。免疫组化法检测MMP 14在LUSQ临床标本中的表达。这些结果提示miR-150- 5 p的下调和MMP 14的过度表达可能在LUSQ的发病机制中起重要作用。
In the present study, in order to elucidate the aggressive nature of lung squamous cell carcinoma (LUSQ), we investigated the oncogenic RNA networks regulated by antitumor microRNAs (miRNAs or miRs) in LUSQ cells. The analysis of our original miRNA expression signatures of human cancers revealed that microRNA-150-5p (miR-150-5p) was downregulated in various types of cancer, indicating that miR-150-5p acts as an antitumor miRNA by targeting several oncogenic genes. Thus, the aims of this study were to investigate the antitumor roles of miR-150-5p in LUSQ cells and to identify oncogenes regulated by miR-150-5p that are involved in the aggressive behavior of LUSQ. The downregulation of miR-150-5p was validated in clinical samples of LUSQ and cell lines (SK-MES-1 and EBC-1). The ectopic overexpression of miR-150-5p significantly suppressed cancer cell aggressiveness. Comprehensive gene expression analyses revealed that miR-150-5p regulated 9 genes in the LUSQ cells. Among these, matrix metalloproteinase 14 (MMP14) was found to be a direct target of miR-150-5p, as shown by luciferase reporter assay. The knockdown of MMP14 using siRNA against MMP14 (si-MMP14) significantly inhibited cancer cell migration and invasion. The overexpression of MMP14 was detected in clinical specimens of LUSQ by immunohistochemistry. On the whole, these findings suggest that the downregulation of miR-150-5p and the overexpression of MMP14 may be deeply involved in the pathogenesis of LUSQ.