METTL3-Driven Maturation of miR-103 Promotes the Progression of Non-Small Cell Lung Cancer

This study aimed to elucidate the molecular mechanism underlying the m6A modification of miR-103 and its role in promoting proliferation and epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance in non-small cell lung cancer (NSCLC).

The expression levels of miR-103 in EGFR-TKI-resistant versus sensitive tissues were analyzed using data from the GEO database, and its potential regulatory pathways were predicted. The effects of miR-103 overexpression or inhibition on NSCLC cell proliferation and drug resistance were evaluated using CCK-8 assays, Transwell migration assays, colony formation assays, and IC50 assays. The influence of miR-103 on the PI3K/ AKT/mTOR signaling axis was investigated through Western blotting, rescue experiments, and dual-luciferase reporter assays. Additionally, the N6-methyladenosine (m6A) modification mechanism of miR-103 was confirmed via methylated RNA immunoprecipitation (MeRIP), RNA pull-down, and RNA immunoprecipitation (RIP) assays.

Bioinformatics analyses demonstrated that miR-103 is significantly upregulated in EGFR-TKI-resistant tissues (p < 0.001) and modulates the PI3K/AKT/mTOR pathway. Compared with parental A549 cells, EGFR-TKI-resistant A549-R cells exhibited markedly elevated miR-103 expression levels (p < 0.001). Overexpression of miR-103 significantly promoted cell proliferation, colony formation, and invasion, while reducing sensitivity to osimertinib (p < 0.001). In contrast, inhibition of miR-103 yielded the opposite effects (p < 0.001). Mechanistically, miR-103 may activate the PI3K/AKT/mTOR pathway by inhibiting PTEN expression, thus promoting NSCLC proliferation and resistance. Moreover, METTL3 enhances the stability and expression of miR-103 via catalyzing its m6A modification. Targeting METTL3 inhibits NSCLC proliferation and drug resistance by downregulating miR-103 and blocking the PI3K/AKT/mTOR axis.

METTL3-mediated m6A modification of miR-103 facilitates NSCLC progression and EGFR-TKI resistance through activation of the PI3K/AKT/mTOR signaling pathway. Targeting METTL3 and miR-103 represents a promising therapeutic strategy for NSCLC treatment.