抑制 microRNA-454 通过促进 N-myc 下游调节基因 2 和抑制 WNT/β-连环蛋白信号通路来阻碍前列腺癌细胞的增殖和侵袭。
Suppression of microRNA-454 impedes the proliferation and invasion of prostate cancer cells by promoting N-myc downstream-regulated gene 2 and inhibiting WNT/β-catenin signaling.
机构信息
Department of Urology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
Department of Urology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
出版信息
Biomed Pharmacother. 2018 Jan;97:120-127. doi: 10.1016/j.biopha.2017.10.115. Epub 2017 Nov 6.
MicroRNA-454 (miR-454) is emerging as critical regulator in tumorigenesis; it may function as an oncogene or a tumor suppressor. However, the role of miR-454 in prostate cancer remains unknown. In this study, we aimed to investigate the function and molecular mechanisms of miR-454 in prostate cancer. We found that miR-454 was highly expressed in prostate cancer tissues and cell lines (*p<0.05), as detected by real-time quantitative polymerase chain reaction (RT-qPCR). Cell counting kit-8 assay, colony formation assay and cell invasion assay showed that the inhibition of miR-454 significantly suppressed prostate cancer cell proliferation and invasion (*p<0.05), whereas the overexpression of miR-454 markedly promoted prostate cancer cell proliferation and invasion (*p<0.05). Bioinformatics analysis showed that N-myc downstream-regulated gene 2 (NDRG2), a well-known tumor suppressor, was identified as a potential target gene of miR-454. Dual-luciferase reporter assay showed that miR-454 directly targeted the 3'-untranslated region of NDRG2. RT-qPCR and western blot showed that miR-454 overexpression significantly decreased NDRG2 expression (*p<0.05), whereas miR-454 inhibition markedly promoted NDRG2 expression (*p<0.05). Spearman's correlation analysis showed that miR-454 expression was inversely correlated with NDRG2 expression in prostate cancer tissues (r=-0.8932; p<0.0001). Moreover, miR-454 inhibition significantly suppressed the protein expression of β-catenin (*p<0.05) and blocked the activation of WNT signaling (*p<0.05). In addition, small interfering RNA mediated NDRG2 knockdown significantly reversed the antitumor effect of miR-454 inhibition on prostate cancer cell proliferation and invasion (*p<0.05). Taken together, these results reveal an oncogenic role of miR-454, which promotes prostate cancer cell proliferation and invasion by downregulation of NDRG2. These results also suggest miR-454 as a potential therapeutic target for the treatment of prostate cancer.
微小 RNA-454 (miR-454) 作为肿瘤发生过程中的关键调节因子而崭露头角；它可能作为癌基因或肿瘤抑制因子发挥作用。然而，miR-454 在前列腺癌中的作用尚不清楚。在本研究中，我们旨在研究 miR-454 在前列腺癌中的功能和分子机制。我们发现，实时定量聚合酶链反应 (RT-qPCR) 检测到 miR-454 在前列腺癌组织和细胞系中高表达（*p<0.05）。细胞计数试剂盒-8 检测、集落形成检测和细胞侵袭检测表明，miR-454 的抑制显著抑制前列腺癌细胞的增殖和侵袭（*p<0.05），而 miR-454 的过表达显著促进前列腺癌细胞的增殖和侵袭（*p<0.05）。生物信息学分析表明，N-myc 下游调节基因 2（NDRG2），一种已知的肿瘤抑制因子，被鉴定为 miR-454 的潜在靶基因。双荧光素酶报告基因检测表明，miR-454 可直接靶向 NDRG2 的 3'非翻译区。RT-qPCR 和 Western blot 表明，miR-454 过表达显著降低 NDRG2 表达（*p<0.05），而 miR-454 抑制显著促进 NDRG2 表达（*p<0.05）。Spearman 相关性分析表明，miR-454 表达与前列腺癌组织中 NDRG2 表达呈负相关（r=-0.8932；p<0.0001）。此外，miR-454 抑制显著抑制 β-catenin 蛋白表达（*p<0.05）并阻断 WNT 信号通路的激活（*p<0.05）。此外，小干扰 RNA 介导的 NDRG2 敲低显著逆转了 miR-454 抑制对前列腺癌细胞增殖和侵袭的抗肿瘤作用（*p<0.05）。综上所述，这些结果揭示了 miR-454 的致癌作用，它通过下调 NDRG2 促进前列腺癌细胞的增殖和侵袭。这些结果还表明 miR-454 可作为治疗前列腺癌的潜在治疗靶点。
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