Ma Fei, Song Hongjiang, Guo Baoliang, Zhang Yuxin, Zheng Yasheng, Lin Chengchun, Wu Ying, Guan Guijie, Sha Ruihua, Zhou Qingxin, Wang Dejun, Zhou Xinglu, Li Juan, Qiu Xiaohui
Department of Endoscopy, The Affiliated Cancer Hospital, Harbin Medical University, Harbin, China.
Department of Gastrointestinal Surgery, The Affiliated Cancer Hospital, Harbin Medical University, Harbin, China.
Oncotarget. 2015 Jul 10;6(19):17404-16. doi: 10.18632/oncotarget.3744.
MicroRNAs (miRs) function as key regulators of gene expression and their deregulation is associated with the carcinogenesis of various cancers. In the present study, we investigated the biological role and mechanism of miR-361-5p in colorectal carcinoma (CRC) and gastric cancer (GC). We showed that microRNA-361-5p (miR-361-5p) was down-regulated in CRC and GC in comparison to the controls. Meanwhile, the expression levels of miR-361-5p negatively correlated with lung metastasis and prognosis in clinical CRC patients. Overexpression of miR-361-5p markedly suppressed proliferation, migration and invasion of cancer cells. Additionally, this phenotype could be partially rescued by the ectopic expression of staphylococcal nuclease domain containing-1 (SND1). SND1 was identified as a target of miR-361-5p using bioinformatics analysis and in vitro luciferase reporter assays. In turn, SND1 bound to pre-miR-361-5p and suppressed the expression of miR-361-5p, thus exerting a feedback loop. Most interestingly, in vivo studies showed that restoration of miR-361-5p significantly inhibited tumor growth and especially the lung metastasis in nude mice. Therefore, it could be concluded that miR-361-5p functions as a tumor-suppressive miRNA through directly binding to SND1, highlighting its potential as a novel agent for the treatment of patients with CRC and GC.
微小RNA(miR)作为基因表达的关键调节因子,其失调与多种癌症的发生相关。在本研究中,我们调查了miR-361-5p在结直肠癌(CRC)和胃癌(GC)中的生物学作用及机制。我们发现,与对照组相比,微小RNA-361-5p(miR-361-5p)在CRC和GC中表达下调。同时,miR-361-5p的表达水平与临床CRC患者的肺转移及预后呈负相关。miR-361-5p的过表达显著抑制癌细胞的增殖、迁移和侵袭。此外,含葡萄球菌核酸酶结构域-1(SND1)的异位表达可部分挽救此表型。通过生物信息学分析和体外荧光素酶报告基因检测,SND1被确定为miR-361-5p的一个靶标。反过来,SND1与pre-miR-361-5p结合并抑制miR-361-5p的表达,从而形成一个反馈环。最有趣的是,体内研究表明,miR-361-5p的恢复显著抑制裸鼠肿瘤生长,尤其是肺转移。因此,可以得出结论,miR-361-5p通过直接结合SND1发挥肿瘤抑制性miRNA的作用,突出了其作为治疗CRC和GC患者新型药物的潜力。