通过m6A修饰，MEETL3参与肝内胆管癌细胞增殖、侵袭和迁移的机制。

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research Pub Date : 2025-01-15 DOI:10.1016/j.yexcr.2024.114353

Xinmiao Jiang , Hui Tan

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引用次数: 0

摘要

肝内胆管癌（ICC）是一种原发性侵袭性恶性肿瘤。本研究旨在探讨甲基转移酶样3 （METTL3）介导的m6A修饰在ICC细胞中的作用，并为ICC治疗提供新的靶点。检测细胞中METTL3/YTH n6 -甲基腺苷RNA结合蛋白2 (YTHDF2)/Nedd4家族相互作用蛋白1 （NDFIP1）水平。评估细胞活力、增殖、侵袭和迁移。分析METTL3、YTHDF2和m6A在NDFIP1 mRNA上的富集程度。测定mRNA的稳定性。将抑制YTHDF2或NDFIP1与si-METTL3联合进行机制验证。验证了METTL3在体内的作用。METTL3在ICC细胞中过表达。METTL3的沉默抑制了ICC细胞的恶性行为，而METTL3的过表达则逆转了这种恶性行为。METTL3增加了m6A对NDFIP1 mRNA的修饰，促进YTHDF2对m6A的识别，促进NDFIP1 mRNA的降解，从而抑制NDFIP1的表达。YTHDF2抑制增加NDFIP1 mRNA水平。NDFIP1下调部分逆转了si-METTL3对ICC细胞行为的抑制作用，NDFIP1过表达部分逆转了METTL3对ICC细胞行为的促进作用。METTL3下调通过增加NDFIP1表达抑制ICC生长。综上所述，METTL3通过以ythdf2依赖的方式促进NDFIP1 mRNA的降解，从而加剧ICC细胞的增殖、侵袭和迁移。

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Mechanism of METTL3 in the proliferation, invasion, and migration of intrahepatic cholangiocarcinoma cells via m6A modification

Intrahepatic cholangiocarcinoma (ICC) is a primary invasive malignant tumor. This study was conducted to explore the role of methyltransferase-like 3 (METTL3)-mediated m6A modification in ICC cells and provide novel targets for ICC treatment. Levels of METTL3/YTH N6-methyladenosine RNA binding protein 2 (YTHDF2)/Nedd4 family interacting protein 1 (NDFIP1) in cells were determined. Cell viability, proliferation, invasion, and migration were evaluated. The enrichments of METTL3, YTHDF2, and m6A on NDFIP1 mRNA were analyzed. The mRNA stability was determined. Inhibition of YTHDF2 or NDFIP1 was combined with si-METTL3 to confirm the mechanism. The role of METTL3 in vivo was verified. METTL3 was overexpressed in ICC cells. METTL3 silencing suppressed ICC cell malignant behaviors, which were reversed by METTL3 overexpression. METTL3 increased m6A modification on NDFIP1 mRNA, facilitated YTHDF2 recognition of m6A, and promoted NDFIP1 mRNA degradation, thereby suppressing NDFIP1 expression. YTHDF2 inhibition increased NDFIP1 mRNA levels. NDFIP1 downregulation partially reversed the inhibitory effects of si-METTL3 on ICC cell behaviors, while NDFIP1 overexpression partially reversed the promotive effects of METTL3 on ICC cell behaviors. METTL3 downregulation suppressed ICC growth by increasing NDFIP1 expression. In conclusion, METTL3 aggravates ICC cell proliferation, invasion, and migration by promoting the degradation of NDFIP1 mRNA in a YTHDF2-dependent manner.

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来源期刊

Experimental cell research 医学-细胞生物学

CiteScore

7.20

自引率

0.00%

发文量

295

审稿时长

30 days

期刊介绍： Our scope includes but is not limited to areas such as: Chromosome biology; Chromatin and epigenetics; DNA repair; Gene regulation; Nuclear import-export; RNA processing; Non-coding RNAs; Organelle biology; The cytoskeleton; Intracellular trafficking; Cell-cell and cell-matrix interactions; Cell motility and migration; Cell proliferation; Cellular differentiation; Signal transduction; Programmed cell death.