Therapeutic Effects of MicroRNA-582-5p and -3p on the Inhibition of Bladder Cancer Progression
Therapeutic Effects of MicroRNA-582-5p and -3p on the Inhibition of Bladder Cancer Progression
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DOI：
10.1038/mt.2012.269
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发表时间：
2013-03-01
影响因子：
12.4
通讯作者：
Ochiya, Takahiro
中科院分区：
文献类型：
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作者：
Uchino, Keita;Takeshita, Fumitaka;Ochiya, Takahiro
许多研究表明microRNA（miRNAs）的异常表达与疾病的进展有关，并将miRNAs作为治疗干预的靶点。然而，在RNA干扰（RNAi）治疗中miRNA引导链和过客链的双功能机制尚未阐明。在这里，我们表明，miRNA（miR）-582-5p和-3p在高级别膀胱癌临床样本中强烈降低，在体外和体内调节肿瘤进展。值得注意的是，miR-582- 5 p或-3p的过表达降低了UM-UC-3人膀胱癌细胞的增殖和侵袭。此外，经尿道注射合成的miR-582分子抑制膀胱癌动物模型中的肿瘤生长和转移。最有趣的是，我们的研究揭示了miR-582- 5 p和-3p的两条链抑制了同一组靶基因的表达，如蛋白香叶基香叶基转移酶I型β亚基（PGGT 1B），富含亮氨酸的重复激酶2（LRRK 2）和DIX结构域1（DIXDC 1）。使用小干扰RNA（siRNA）敲低这些基因导致UM-UC-3的细胞生长和侵袭性的抑制。这些发现揭示了涉及单个miRNA的两条链的肿瘤抑制的独特调控途径，这是浸润性膀胱癌治疗中的潜在治疗靶点。
Many reports have indicated that the abnormal expression of microRNAs (miRNAs) is associated with the progression of disease and have identified miRNAs as attractive targets for therapeutic intervention. However, the bifunctional mechanisms of miRNA guide and passenger strands in RNA interference (RNAi) therapy have not yet been clarified. Here, we show that miRNA (miR)-582-5p and -3p, which are strongly decreased in high-grade bladder cancer clinical samples, regulate tumor progression in vitro and in vivo. Significantly, the overexpression of miR-582-5p or -3p reduced the proliferation and invasion of UM-UC-3 human bladder cancer cells. Furthermore, transurethral injections of synthetic miR-582 molecule suppressed tumor growth and metastasis in an animal model of bladder cancer. Most interestingly, our study revealed that both strands of miR-582-5p and -3p suppressed the expression of the same set of target genes such as protein geranylgeranyltransferase type I beta subunit (PGGT1B), leucine-rich repeat kinase 2 (LRRK2) and DIX domain containing 1 (DIXDC1). Knockdown of these genes using small interfering RNA (siRNA) resulted in the inhibition of cell growth and invasiveness of UM-UC-3. These findings uncover the unique regulatory pathway involving tumor suppression by both strands of a single miRNA that is a potential therapeutic target in the treatment of invasive bladder cancer.