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miR-593 通过靶向 SLUG 相关信号通路抑制非小细胞肺癌细胞的增殖、侵袭并促进其凋亡。

miR‑593 inhibits proliferation and invasion and promotes apoptosis in non‑small cell lung cancer cells by targeting SLUG‑associated signaling pathways.

机构信息

Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110033, P.R. China.

出版信息

Mol Med Rep. 2019 Dec;20(6):5172-5182. doi: 10.3892/mmr.2019.10776. Epub 2019 Oct 29.

Abstract

Increasing evidence suggests that microRNAs (miRNAs or miRs) serve a critical role in tumor development. However, the role of miRNAs in non‑small cell lung cancer (NSCLC) progression remains largely unknown. The present study observed that miR‑593 was significantly impaired in patients with NSCLC and was a novel regulator of NSCLC progression. Patients whose tumors had high expression levels of miR‑593 had longer overall survival than patients whose tumors had low levels of miR‑593 expression (P=0.0219). miR‑593 expression levels were inversely correlated with zinc finger protein SNAI2 (SLUG) messenger RNA (mRNA) levels in 87 clinical tissue specimens of NSCLC (P<0.001). A luciferase assay demonstrated that miR‑593 interacted with the binding sites present in the SLUG 3'‑untranslated region and reduced the expression of SLUG. Introduction of a miR‑593 mimic suppressed cell proliferation by inactivating the SLUG/protein kinase B (Akt)/cyclin D1/CDK4 or CDK6 signaling pathway, while it induced apoptosis by activating the SLUG/Akt/Bcl‑2/BAX signaling pathway. Furthermore, introduction of a miR‑593 mimic recovered the expression of E‑cadherin at the protein and mRNA level, and inhibited cell migration and invasion. In conclusion, these results indicated that miR‑593 may act as a tumor suppressor in NSCLC to decelerate cancer aggressiveness by inhibiting SLUG expression.

摘要

越来越多的证据表明,微小 RNA(miRNA 或 miR)在肿瘤发生中起着关键作用。然而,miRNA 在非小细胞肺癌(NSCLC)进展中的作用在很大程度上尚不清楚。本研究观察到 miR-593 在 NSCLC 患者中显著受损,是 NSCLC 进展的新型调节因子。miR-593 表达水平高的患者总生存期长于 miR-593 表达水平低的患者(P=0.0219)。在 87 例 NSCLC 临床组织标本中,miR-593 表达水平与锌指蛋白 SNAI2(SLUG)信使 RNA(mRNA)水平呈负相关(P<0.001)。荧光素酶报告基因检测表明,miR-593 与 SLUG 3'UTR 中的结合位点相互作用,降低 SLUG 的表达。miR-593 模拟物的引入通过失活 SLUG/蛋白激酶 B(Akt)/细胞周期蛋白 D1/CDK4 或 CDK6 信号通路抑制细胞增殖,而通过激活 SLUG/Akt/Bcl-2/BAX 信号通路诱导细胞凋亡。此外,miR-593 模拟物的引入恢复了 E-钙粘蛋白在蛋白和 mRNA 水平的表达,并抑制了细胞迁移和侵袭。综上所述,这些结果表明,miR-593 可能作为 NSCLC 中的肿瘤抑制因子发挥作用,通过抑制 SLUG 表达来减缓癌症侵袭性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7d1/6854539/7c131e8214d7/MMR-20-06-5172-g00.jpg

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