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微小RNA-424-5p通过直接靶向细胞周期检查点激酶1（CHEK1）并激活细胞周期途径来抑制肝癌的肿瘤生长和进展。

MiR-424-5p suppresses tumor growth and progression by directly targeting CHEK1 and activating cell cycle pathway in Hepatocellular Carcinoma.

作者信息

Yin Chunlin, Sun Yuansong, Li He, Zheng Xianxian

机构信息

Department of Emergency, The Second Affiliated Hospital of Anhui Medical University,Anhui Hefei, 230601, China.

Research Center of Minimally Invasive Intervention, Anhui Medical University, Anhui Hefei, 230601, China.

出版信息

Heliyon. 2024 Sep 11;10(18):e37769. doi: 10.1016/j.heliyon.2024.e37769. eCollection 2024 Sep 30.

DOI:10.1016/j.heliyon.2024.e37769
PMID:39309825
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11416538/
Abstract

OBJECTIVES

The aim of this study is to elucidate the functional mechanism of the miRNA-424-5p/CHEK1 pathway in hepatocellular carcinoma (HCC), thereby offering novel insights for the development of targeted therapeutic strategies for HCC.

METHODS

We employed a combination of bioinformatics analysis and data from the GEO to construct a regulatory network between miRNA and mRNA. Real-time quantitative polymerase chain reaction (RT-qPCR) was utilized to assess the expression levels of miR-424-5p and CHEK1. Protein expression of CHEK1 was determined using Western blot analysis. The targeting relationship between miR-424-5p and CHEK1 was validated through a dual-luciferase reporter assay. Furthermore, the effects of miR-424-5p on HCC cell proliferation, migration, and invasion were evaluated using the Cell Counting Kit-8 assay, wound healing assay, and Transwell invasion assay, respectively. Apoptosis of HCC cells was measured by flow cytometry.

RESULTS

Bioinformatics analysis revealed that miR-424-5p was significantly downregulated, while CHEK1 was upregulated respectively in GEO dataset. Furthermore, this inverse expression pattern was observed in both HCC tissues and cell lines. Specifically, downregulation of miR-424-5p was found to promote the proliferation, migration, and invasion of HCC cells, while also inhibiting their apoptosis. The dual-luciferase reporter assay confirmed a direct targeting relationship between miR-424-5p and CHEK1. Inhibition of miR-424-5p was shown to counteract the suppressive effects on HCC cell proliferation, migration, and invasion that result from CHEK1 silencing. Additionally, experimental verification indicated that the activation of the cell cycle pathway is implicated in the oncogenic function of miR-424-5p/CHEK1 in HCC.

CONCLUSIONS

The present study demonstrates that miR-424-5p exerts a suppressive effect on HCC cell proliferation, migration, and invasion by downregulating the expression of CHEK1. This finding may offer a theoretical foundation for improving the prognosis and developing novel therapeutic strategies for HCC patients.

摘要

目的

本研究旨在阐明miRNA - 424 - 5p/CHEK1通路在肝细胞癌（HCC）中的功能机制，从而为HCC靶向治疗策略的开发提供新的见解。

方法

我们结合生物信息学分析和来自基因表达综合数据库（GEO）的数据构建miRNA与mRNA之间的调控网络。采用实时定量聚合酶链反应（RT - qPCR）评估miR - 424 - 5p和CHEK1的表达水平。使用蛋白质印迹分析确定CHEK1的蛋白表达。通过双荧光素酶报告基因检测验证miR - 424 - 5p与CHEK1之间的靶向关系。此外，分别使用细胞计数试剂盒 - 8检测、伤口愈合检测和Transwell侵袭检测评估miR - 424 - 5p对HCC细胞增殖、迁移和侵袭的影响。通过流式细胞术检测HCC细胞的凋亡情况。

结果

生物信息学分析显示，在GEO数据集中miR - 424 - 5p显著下调，而CHEK1上调。此外，在HCC组织和细胞系中均观察到这种相反的表达模式。具体而言，发现miR - 424 - 5p的下调促进了HCC细胞的增殖、迁移和侵袭，同时也抑制了它们的凋亡。双荧光素酶报告基因检测证实了miR - 424 - 5p与CHEK1之间存在直接靶向关系。结果表明，抑制miR - 424 - 5p可抵消CHEK1沉默对HCC细胞增殖、迁移和侵袭的抑制作用。此外，实验验证表明细胞周期通路的激活与miR - 424 - 5p/CHEK1在HCC中的致癌功能有关。

结论

本研究表明，miR - 424 - 5p通过下调CHEK1的表达对HCC细胞的增殖、迁移和侵袭发挥抑制作用。这一发现可能为改善HCC患者的预后和开发新的治疗策略提供理论基础。

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