微小RNA-186-5p通过靶向甲基转移酶样3来抑制肝细胞癌进展，甲基转移酶样3可调节m6A介导的卵泡抑素样蛋白5的稳定性。
MiR-186-5p prevents hepatocellular carcinoma progression by targeting methyltransferase-like 3 that regulates m6A-mediated stabilization of follistatin-like 5.
作者信息
Ma Shuoshuo, Chen Fangfang, Lin Chuanle, Sun Wanliang, Wang Dongdong, Zhou Shuo, Chang ShiRu, Lu Zheng, Zhang Dengyong
机构信息
Department of General Surgery, The First Affiliated Hospital of BengBu Medical College, BengBu, 233000, China.
Liver Transplantation Center and Hepatobiliary and Pancreatic Surgery, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
出版信息
Heliyon. 2024 Feb 29;10(5):e26767. doi: 10.1016/j.heliyon.2024.e26767. eCollection 2024 Mar 15.
BACKGROUND
Hepatocellular carcinoma (HCC) is a multistep process involving sophisticated genetic, epigenetic, and transcriptional changes. However, studies on microRNA (miRNA)'s regulatory effects of N6-methyladenosine (m6A) modifications on HCC progression are limited.
METHODS
Cell Counting Kit-8 (CCK-8), clone formation, and Transwell assays were used to investigate changes in cancer cell proliferation, invasion, and migration. RNA m6A levels were verified using methylated RNA immunoprecipitation. Luciferase reporter assay was used to study the potential binding between miRNAs and mRNA. A mouse tumor transplant model was established to study the changes in tumor progression.
RESULTS
Follistatin-like 5 (FSTL5) was significantly downregulated in HCC and inhibited its further progression. Additionally, methyltransferase-like 3 (METTL3) reduced FSTL5 mRNA stability in an m6A-YTH domain family 2(YTHDF2)-dependent manner. Functional experiments revealed that METTL3 downregulation inhibited HCC progression by upregulating FSTL5 and . Luciferase reporter assay verified that miR-186-5p directly targets METTL3. Additionally, miR-186-5p inhibits the proliferation, migration, and invasion of HCC cells by downregulating METTL3 expression.
CONCLUSIONS
The miR-186-5p/METTL3/YTHDF2/FSTL5 axis may offer new directions for targeted HCC therapy.
背景
肝细胞癌（HCC）是一个涉及复杂基因、表观遗传和转录变化的多步骤过程。然而，关于微小RNA（miRNA）对N6-甲基腺苷（m6A）修饰在HCC进展中的调控作用的研究有限。
方法
采用细胞计数试剂盒-8（CCK-8）、克隆形成和Transwell实验来研究癌细胞增殖、侵袭和迁移的变化。使用甲基化RNA免疫沉淀法验证RNA的m6A水平。荧光素酶报告基因检测用于研究miRNA与mRNA之间的潜在结合。建立小鼠肿瘤移植模型以研究肿瘤进展的变化。
结果
卵泡抑素样蛋白5（FSTL5）在HCC中显著下调，并抑制其进一步进展。此外，甲基转移酶样蛋白3（METTL3）以一种依赖m6A-YTH结构域家族2（YTHDF2）的方式降低FSTL5 mRNA的稳定性。功能实验表明，下调METTL3通过上调FSTL5抑制HCC进展。荧光素酶报告基因检测证实miR-186-5p直接靶向METTL3。此外，miR-186-5p通过下调METTL3表达抑制HCC细胞的增殖、迁移和侵袭。
结论
miR-186-5p/METTL3/YTHDF2/FSTL5轴可能为HCC的靶向治疗提供新的方向。
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