MicroRNA miR-4779 suppresses tumor growth by inducing apoptosis and cell cycle arrest through direct targeting of PAK2 and CCND3.
MicroRNA miR-4779 suppresses tumor growth by inducing apoptosis and cell cycle arrest through direct targeting of PAK2 and CCND3.
复制标题
DOI：
10.1038/s41419-017-0100-x
复制
发表时间：
2018-01-23
影响因子：
9
通讯作者：
Kwon H
中科院分区：
文献类型：
--
作者：
Koo KH;Kwon H
根据其靶基因的功能，microRNAs(MiRNAs)既可以作为肿瘤抑制因子，也可以作为癌基因。因此，miRNAs代表了一种通过靶向onco-miRNAs或模仿肿瘤抑制基因miRNAs来预防和治疗癌症的新的治疗策略。在此，我们发现了新的肿瘤抑制基因miRNAs，并对其分子机制进行了研究。为了确定新的肿瘤抑制基因miRNAs，我们使用了532个人miRNA模拟文库，并用MTS法测定了细胞的存活率。用细胞周期分析、细胞凋亡、集落形成和软琼脂实验分析miR-4779的功能。用TargetScan和miRDB数据库预测miR-4779的目的基因，并用荧光素酶分析进行确认。采用定量逆转录聚合酶链式反应和免疫印迹分析检测结肠癌组织中miR-4779和靶基因的表达水平。最后，评价miR-4779对HCT116移植瘤的体内抑制作用。在本研究中，miR-4779通过诱导细胞凋亡和细胞周期停滞来抑制癌细胞的生长，并将可能的生存因子PAK2和CCND3确定为miR-4779的直接靶点。在随后的实验中，PAK2基因敲除导致细胞周期停滞，CCND3基因敲除诱导细胞周期停滞和细胞凋亡。此外，miR-4779在体内HCT116异种移植模型中抑制肿瘤生长和肿瘤形成。最后，miR-4779在10例结肠癌组织中有9例低表达，而PAK2和CCND3在结肠癌组织中显著高表达。新型肿瘤抑制剂miR-4779通过直接靶向PAK2和CCND3，通过细胞周期停滞和凋亡来抑制癌细胞的生长。目前的数据表明miR-4779作为基于miRNA的癌症治疗的治疗靶点的潜力。
Depending on the function of their target genes, microRNAs (miRNAs) act as either tumor suppressors or oncogenes. Therefore, miRNAs represent a novel therapeutic strategy for prevention and management of cancer by targeting of onco-miRNAs or mimicking of tumor suppressor miRNAs. Herein, we identified novel tumor suppressor miRNAs and investigated their molecular mechanisms. To identify novel tumor suppressor miRNAs, we used 532 human miRNA mimic libraries and measured cell viability using MTS assays. The function of miR-4779 was then analyzed using cell cycle analyses and apoptosis, colony forming, and soft agar assays. Target genes of miR-4779 were predicted using TargetScan and miRDB databases and were confirmed using luciferase assays. Levels of miR-4779 and target genes in colon cancer tissue samples from patients were evaluated using qRT-PCR and western blotting analyses. Finally, in vivo tumor suppressive effects of miR-4779 were evaluated in HCT116 xenografts. In this study, miR-4779 inhibited cancer cell growth by inducing apoptosis and cell cycle arrest, and the putative survival factors PAK2 and CCND3 were identified as direct targets of miR-4779. In subsequent experiments, PAK2 knockdown induced cell cycle arrest and CCND3 knockdown induced cell cycle arrest and apoptosis. In addition, miR-4779 suppressed tumor growth and tumorigenesis in an in vivo HCT116 xenograft model. Finally, miR-4779 expression was low in 9 of 10 colon cancer tissues, whereas PAK2 and CCND3 expressions were significantly high in colon cancer tissues. The novel tumor suppressor miR-4779 inhibits cancer cell growth via cell cycle arrest and apoptosis by directly targeting PAK2 and CCND3. The present data indicate the potential of miR-4779 as a therapeutic target for miRNA-based cancer therapy.
登录
查看更多内容
影响因子：
8.8
作者：
通讯作者：
--
影响因子：
2.6
作者：
Gao C;Ma T;Pang L;Xie R
通讯作者：
Xie R
影响因子：
64.8
作者：
Lu, J;Getz, G;Golub, TR
通讯作者：
Golub, TR
影响因子：
64.8
作者：
MANSER, E;LEUNG, T;LIM, L
通讯作者：
LIM, L
影响因子：
4.8
作者：
Jakobi, R;Moertl, E;Koeppel, MA
通讯作者：
Koeppel, MA