Upregulation of MicroRNA-21 promotes tumorigenesis of prostate cancer cells by targeting KLF5
Upregulation of MicroRNA-21 promotes tumorigenesis of prostate cancer cells by targeting KLF5
复制标题
MicroRNA-21的上调通过靶向KLF5促进前列腺癌细胞的肿瘤发生
DOI：
10.1080/15384047.2019.1599659
复制
发表时间：
2019-08-03
影响因子：
3.6
通讯作者：
Lyu, Jianxin
中科院分区：
文献类型：
--
作者：
Guan, Chen;Zhang, Lingling;Lyu, Jianxin
摘要前列腺癌（PCa）是男性第二常见的新发癌症。雄激素剥夺疗法已被广泛用于抑制PCa生长，但最终在许多患者中失败。雄激素受体及其下游分子如microRNA可能是有希望的治疗靶点。我们的目的是研究miR-21在PCa肿瘤发生中的作用。我们从TCGA数据库中发现miR-21是PCa患者的不利因素，并且与肿瘤分级呈正相关。miR-21在雄激素非依赖性前列腺癌细胞中的表达高于雄激素依赖性前列腺癌细胞。miR-21的过表达促进雄激素依赖性和非依赖性PCa细胞增殖、迁移、侵袭和抗凋亡。此外，增加的miR-21表达促进小鼠异种移植物生长。我们通过生物信息学分析鉴定了9个在PCa肿瘤和正常组织中差异表达的基因，这些基因可能是miR-21的潜在靶点。我们证明miR-21直接靶向KLF 5并抑制PCa中KLF 5 mRNA和蛋白水平。STRING和功能富集分析结果表明，GSK 3B可能受到KLF 5的调控。我们的研究结果表明，miR-21通过直接靶向KLF 5促进PCa细胞的肿瘤发生。这些生物学效应是通过GSK 3B的上调和AKT信号通路的激活介导的。
ABSTRACT Prostate cancer (PCa) is the second frequently newly diagnosed cancer in men. Androgen deprivation therapy has been widely used to inhibit PCa growth but eventually fails in many patients. Androgen receptor and its downstream molecules like microRNAs could be promising therapeutic targets. We aimed to investigate the involvement of miR-21 in PCa tumorigenesis. We found that miR-21 was an unfavorable factor and correlated positively with tumor grade in PCa patients from TCGA database. MiR-21 was more highly expressed in androgen-independent PCa cells than in androgen-dependent PCa cells. Overexpression of miR-21 promoted androgen-dependent and -independent PCa cell proliferation, migration, invasion, and resistance to apoptosis. Furthermore, increased miR-21 expression promoted mouse xenograft growth. We identified nine genes differentially expressed in PCa tumors and normal tissue which could be potential targets of miR-21 by bioinformatic analyses. We demonstrate that miR-21 directly targeted KLF5 and inhibited KLF5 mRNA and protein levels in PCa. STRING and functional enrichment analysis results suggest that GSK3B might be regulated by KLF5. Our findings demonstrate that miR-21 promotes the tumorigenesis of PCa cells by directly targeting KLF5. These biological effects are mediated through upregulation of GSK3B and activation of the AKT signaling pathway.