MicroRNA-466 inhibits tumor growth and bone metastasis in prostate cancer by direct regulation of osteogenic transcription factor RUNX2.
MicroRNA-466 inhibits tumor growth and bone metastasis in prostate cancer by direct regulation of osteogenic transcription factor RUNX2.
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DOI：
10.1038/cddis.2017.15
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发表时间：
2017-01-26
影响因子：
9
通讯作者：
Majid S
中科院分区：
文献类型：
--
作者：
Colden M;Dar AA;Saini S;Dahiya PV;Shahryari V;Yamamura S;Tanaka Y;Stein G;Dahiya R;Majid S
微小RNA（miRNAs）已成为癌症进展和转移起始的关键参与者，但它们在调节前列腺癌（PCa）向骨转移中的重要性已开始被认识到。我们采用基于内部PCa临床样本、公开可用的TCGA队列、一组细胞系、计算机模拟分析以及一系列体外和体内测定的多模式策略来研究miR-466在PCa中的作用。表达分析显示，与正常组织相比，miR-466在PCa中表达不足。与对照miRNA相比，转移性PCa细胞系中miR-466的重建损害了其致癌功能，例如细胞增殖、迁移/侵袭和诱导的细胞周期停滞以及细胞凋亡。相反，正常前列腺细胞中miR-466的衰减诱导肿瘤发生特征。miR-466通过直接靶向骨相关转录因子RUNX 2抑制PCa生长和转移。miR-466的过表达引起RUNX 2靶基因的整合网络的显著下调，所述靶基因例如骨桥蛋白、骨钙素、ANGPT、MMP 11（包括Fyn、pAkt、FAK和波形蛋白），其已知参与迁移、侵袭、血管生成、EMT和转移。异种移植模型表明，miR-466抑制原发性原位肿瘤生长和自发转移到骨。受试者工作曲线和Kaplan-Meier分析显示，miR-466表达可以区分恶性和正常前列腺组织;并且可以预测生化复发。总之，我们的数据强烈表明miR-466介导的RUNX 2衰减作为一种新的治疗方法来调节PCa生长，特别是骨转移。这项研究是第一份记录miR-466在前列腺癌中的抗骨转移作用和临床意义的报告。
MicroRNAs (miRNAs) have emerged as key players in cancer progression and metastatic initiation yet their importance in regulating prostate cancer (PCa) metastasis to bone has begun to be appreciated. We employed multimodal strategy based on in-house PCa clinical samples, publicly available TCGA cohorts, a panel of cell lines, in silico analyses, and a series of in vitro and in vivo assays to investigate the role of miR-466 in PCa. Expression analyses revealed that miR-466 is under-expressed in PCa compared to normal tissues. Reconstitution of miR-466 in metastatic PCa cell lines impaired their oncogenic functions such as cell proliferation, migration/invasion and induced cell cycle arrest, and apoptosis compared to control miRNA. Conversely, attenuation of miR-466 in normal prostate cells induced tumorigenic characteristics. miR-466 suppressed PCa growth and metastasis through direct targeting of bone-related transcription factor RUNX2. Overexpression of miR-466 caused a marked downregulation of integrated network of RUNX2 target genes such as osteopontin, osteocalcin, ANGPTs, MMP11 including Fyn, pAkt, FAK and vimentin that are known to be involved in migration, invasion, angiogenesis, EMT and metastasis. Xenograft models indicate that miR-466 inhibits primary orthotopic tumor growth and spontaneous metastasis to bone. Receiver operating curve and Kaplan–Meier analyses show that miR-466 expression can discriminate between malignant and normal prostate tissues; and can predict biochemical relapse. In conclusion, our data strongly suggests miR-466-mediated attenuation of RUNX2 as a novel therapeutic approach to regulate PCa growth, particularly metastasis to bone. This study is the first report documenting the anti-bone metastatic role and clinical significance of miR-466 in prostate cancer.