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

• Published in: Experimental cell research 2025-01, Vol.444 (2), p.114353, Article 114353
• Main Authors: Jiang, Xinmiao, Tan, Hui
• Format: Article
• Language: English
• Subjects: Intrahepatic cholangiocarcinoma; Invasion and migration; m6A modification; METTL3; Proliferation
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2024.114353

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. •METTL3 promotes ICC cell proliferation, invasion, and migration.•Downregulation of METTL3 inhibits ICC cell proliferation, invasion, and migration.•METTL3 increases m6A modification on NDFIP1 mRNA and decreases NDFIP1 stability.•YTHDF2 recognizes m6A and degrades mRNA, thereby suppressing NDFIP1 expression.•METTL3 promotes ICC cell progression by easing NDFIP1 expression via YTHDF2 pathway.