Regulation of KIF2A by Antitumor miR-451a Inhibits Cancer Cell Aggressiveness Features in Lung Squamous Cell Carcinoma
Regulation of KIF2A by Antitumor miR-451a Inhibits Cancer Cell Aggressiveness Features in Lung Squamous Cell Carcinoma
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DOI：
10.3390/cancers11020258
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发表时间：
2019-02-01
期刊：
影响因子：
5.2
通讯作者：
Inoue, Hiromasa
中科院分区：
文献类型：
--
作者：
Uchida, Akifumi;Seki, Naohiko;Inoue, Hiromasa
在人类基因组中，miR-451 a在染色体区域17q11.2上编码接近miR-144。我们先前的研究表明，前体miR-144的两条链作为抗肿瘤miRNA，并参与肺鳞状细胞癌（LUSQ）的发病机制。在此，我们的目的是研究miR-451 a的功能意义，并确定其在LUSQ细胞中的致癌基因靶向。在LUSQ临床标本中证实了miR-451 a的下调，miR-451 a的低表达与LUSQ患者的不良预后显著相关（总生存期：p = 0.035，无病生存期：p = 0.029）。此外，我们发现miR-451 a的异位表达显著阻断了癌细胞的侵袭性。在LUSQ细胞中，总共有15个推定的致癌基因被miR-451 a调控。在这些目标中，高驱动蛋白家族成员2A（KIF 2A）表达与不良预后显著相关（总生存期：p = 0.043，无病生存期：p = 0.028）。多变量分析显示，KIF 2A表达是LUSQ患者的独立预后因素（风险比= 1.493，p = 0.034）。KIF 2A的异常表达促进了该疾病的恶性转化。基于抗肿瘤miRNA及其靶基因的分析策略是鉴定LUSQ新分子发病机制的有效工具。
In the human genome, miR-451a is encoded close to the miR-144 on chromosome region 17q11.2. Our previous study showed that both strands of pre-miR-144 acted as antitumor miRNAs and were involved in lung squamous cell carcinoma (LUSQ) pathogenesis. Here, we aimed to investigate the functional significance of miR-451a and to identify its targeting of oncogenic genes in LUSQ cells. Downregulation of miR-451a was confirmed in LUSQ clinical specimens, and low expression of miR-451a was significantly associated with poor prognosis of LUSQ patients (overall survival: p = 0.035, disease-free survival: p = 0.029). Additionally, we showed that ectopic expression of miR-451a significantly blocked cancer cell aggressiveness. In total, 15 putative oncogenic genes were shown to be regulated by miR-451a in LUSQ cells. Among these targets, high kinesin family member 2A (KIF2A) expression was significantly associated with poor prognosis (overall survival: p = 0.043, disease-free survival: p = 0.028). Multivariate analysis showed that KIF2A expression was an independent prognostic factor in patients with LUSQ (hazard ratio = 1.493, p = 0.034). Aberrant KIF2A expression promoted the malignant transformation of this disease. Analytic strategies based on antitumor miRNAs and their target oncogenes are effective tools for identification of novel molecular pathogenesis of LUSQ.