Abstract
Esophageal squamous cell carcinoma (ESCC) tissues exhibit abnormal N6-methyladenosine (m6A) modification and regulator levels, but the specific effects of this dysregulation on ESCC remain unclear. WASF3 levels were significantly elevated in ESCC tissues, and ESCC patients with high WASF3 expression had significantly worse prognosis. WASF3 suppressed the proliferation of ESCC cells and inhibited colony formation and cell cycle progression. Mechanistically, METTL3 interacted with WASF3 and mediated m6A modification of its mRNA. Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) enhanced WASF3 translation by binding to the m6A site in its 3' untranslated region, and highly expressed WASF3 activated the mitogen-activated protein kinase (MAPK) signaling pathway by interacting with phosphorylated p38 (p-p38), thereby promoting ESCC progression. Moreover, removal of the m6A modification of WASF3 mRNA inhibited WASF3 expression, ESCC cell proliferation, and abolished the ability of WASF3 to bind to p-p38 and activate MAPK signaling. LNP small interfering RNA targeting WASF3, both alone and in combination with paclitaxel, could successfully suppress ESCC tumorigenesis. Our findings demonstrate that WASF3 plays a pivotal role in ESCC and highlight the functional significance of the METTL3/m6A/WASF3/IGF2BP2 axis in regulating ESCC progression, which could facilitate the development of novel prognostic and therapeutic targets for ESCC.