Regulation of HMGB3 by antitumor miR-205-5p inhibits cancer cell aggressiveness and is involved in prostate cancer pathogenesis
Regulation of HMGB3 by antitumor miR-205-5p inhibits cancer cell aggressiveness and is involved in prostate cancer pathogenesis
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DOI：
10.1038/s10038-017-0371-1
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发表时间：
2018-02-01
影响因子：
3.5
通讯作者：
Seki, Naohiko
中科院分区：
文献类型：
--
作者：
Yamada, Yasutaka;Nishikawa, Rika;Seki, Naohiko
我们最近对前列腺癌（PCa）中microRNA（miRNA）表达特征的测定显示，miR-205- 5 p在PCa组织中显著减少，并且它作为抗肿瘤miRNA发挥作用。本研究的目的是鉴定PCa细胞中受抗肿瘤miR-205- 5 p调控的致癌基因和途径。全基因组基因表达分析和计算机miRNA数据库搜索显示，37个基因是miR-205- 5 p调控的推定靶基因。在这些基因中，在癌症基因组图谱（TCGA）数据库中，7个基因（HMGB 3、CDK 1、MKI 67、CENPF、CDK 1、RHOU和POLR 2D）的表达水平升高与大量患者的无病生存期缩短相关。我们关注高迁移率族蛋白3（HMGB 3），因为它在PC 3细胞中被miR-205- 5 p的异位表达下调最多，并且其表达参与PCa发病机制。荧光素酶报告基因分析表明，HMGB 3在PCa细胞中受miR-205- 5 p的直接调控。使用si-HMGB 3的敲低研究表明，HMGB 3的表达增强PCa细胞的侵袭性。HMGB 3/HMGB 3的过表达在初始PCa和去势抵抗性PCa（CRPC）临床标本中得到证实。分析PCa细胞中抗肿瘤miRNA调控的RNA网络的新方法可能为该疾病的致病机制提供新的见解。
Our recent determination of a microRNA (miRNA) expression signature in prostate cancer (PCa) revealed that miR-205-5p was significantly reduced in PCa tissues and that it acted as an antitumor miRNA. The aim of this study was to identify oncogenic genes and pathways in PCa cells that were regulated by antitumor miR-205-5p. Genome-wide gene expression analyses and in silico miRNA database searches showed that 37 genes were putative targets of miR-205-5p regulation. Among those genes, elevated expression levels of seven in particular (HMGB3, SPARC, MKI67, CENPF, CDK1, RHOU, and POLR2D) were associated with a shorter disease-free survival in a large number of patients in the The Cancer Genome Atlas (TCGA) database. We focused on high-mobility group box 3 (HMGB3) because it was the most downregulated by ectopic expression of miR-205-5p in PC3 cells and its expression was involved in PCa pathogenesis. Luciferase reporter assays showed that HMGB3 was directly regulated by miR-205-5p in PCa cells. Knockdown studies using si-HMGB3 showed that expression of HMGB3 enhanced PCa cell aggressiveness. Overexpression of HMGB3/HMGB3 was confirmed in naive PCa and castration-resistant PCa (CRPC) clinical specimens. Novel approaches to analysis of antitumor miRNA-regulated RNA networks in PCa cells may provide new insights into the pathogenic mechanisms of the disease.