Tumor-suppressive microRNA-223 targets WDR62 directly in bladder cancer
Tumor-suppressive microRNA-223 targets WDR62 directly in bladder cancer
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DOI：
10.3892/ijo.2019.4762
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发表时间：
2019-06-01
影响因子：
5.2
通讯作者：
Enokida, Hideki
中科院分区：
文献类型：
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作者：
Sugita, Satoshi;Yoshino, Hirofumi;Enokida, Hideki
据报道，miRNA-223（miR-223）不仅作为肿瘤抑制因子发挥作用，而且在各种癌细胞中作为致癌microRNA（miRNA或miR）发挥作用。因此，迄今为止，至少就我们所知，miR-223的功能作用尚未阐明。我们之前对临床膀胱癌（BC）标本进行了深度测序分析。结果显示，miR-223在BC中的表达显著下调，表明miR-223在BC中起肿瘤抑制miRNA的作用。本研究的目的是研究miR-223的功能作用，并确定其在BC中的靶点。在我们的临床BC标本中，miR-223的表达水平显著降低。癌症基因组图谱（TCGA）数据库显示miR-223表达与淋巴管浸润和远处转移有关。miR-223表达的恢复显著抑制肿瘤侵袭性，并通过激活BC细胞中的caspase-3/7诱导凋亡。WD重复结构域62（WDR 62）是根据计算机模拟分析的miR-223的候选靶标，先前已提出在神经发育中发挥作用。通过荧光素酶测定证实WDR 62和miR-223之间的直接结合。TCGA数据库显示，WDR 62 mRNA表达与BC中较高的肿瘤分级和分期之间呈正相关。WDR 62基因的敲低可显著抑制肿瘤的侵袭性，并诱导BC细胞凋亡。总的来说，这项研究的发现揭示了一个新的miR-223靶点，致癌WDR 62，并提供了对BC肿瘤发生的见解。
miRNA-223 (miR-223) has been reported to function not only as a tumor suppressor, but also as an oncogenic microRNA (miRNA or miR) in various cancer cells. Therefore, the functional role of miR-223 has not been elucidated to date, at least to the best of our knowledge. We previously performed the deep sequencing analysis of clinical bladder cancer (BC) specimens. It was revealed that miR-223 expression was significantly downregulated in BC, suggesting that miR-223 functions as a tumor suppressor miRNA in BC. The aim of this study was to investigate the functional roles of miR-223 and to identify its targets in BC. The expression levels of miR-223 were significantly decreased in our clinical BC specimens. The Cancer Genome Atlas (TCGA) database indicated that miR-223 expression was related to lymphovascular invasion and distant metastasis. The restoration of miR-223 expression significantly inhibited tumor aggressiveness and induced apoptosis via caspase-3/7 activation in BC cells. WD repeat domain 62 (WDR62), a candidate target of miR-223 according to in silico analyses, has been previously proposed to play a role in neurodevelopment. Direct binding between WDR62 and miR-223 was confirmed by luciferase assay. The TCGA database revealed positive associations between WDR62 mRNA expression and a higher tumor grade and stage in BC. The knockdown of WDR62 significantly inhibited tumor aggressiveness and induced the apoptosis of BC cells. On the whole, the findings of this study reveal a novel miR-223 target, oncogenic WDR62, and provided insight into the oncogenesis of BC.