The role of m6A reader YTHDF2 in lymphangiogenesis via RNF43/WNT5B in oral squamous cell carcinoma

Abstract Lymphangiogenesis significantly contributes to poor prognosis and reduced survival in oral squamous cell carcinoma (OSCC) patients due to lymphatic metastasis. Despite the critical role of N6-methyladenosine (m 6 A)—the most abundant eukaryotic mRNA modification—its influence on OSCC lymphangiogenesis and metastasis remains poorly understood. This study identifies YTHDF2, a key m 6 A reader protein, as markedly upregulated in OSCC and strongly correlated with advanced nodal staging (N-staging). In vitro experiments revealed that YTHDF2 enhances OSCC cell migration and invasion while promoting tube formation and migration in human lymphatic endothelial cells (HLECs). In vivo experiments showed that silencing YTHDF2 reduced lymphatic vessel density in orthotopic tumors and suppressed cervical lymph node metastasis. Mechanistically, integrated RNA-seq and m 6 A-seq data linked YTHDF2-regulated genes to the WNT pathway. YTHDF2 directly binds m 6 A-modified RNF43 mRNA, accelerating its decay and upregulating WNT5B expression. Our findings indicate that WNT5B serves as an important contributor to lymphangiogenesis and lymphatic metastasis in OSCC. These findings elucidate the role of YTHDF2 in OSCC metastasis via m 6 A dependent regulation of the RNF43-WNT5B axis. In addition, WNT5B appears to contribute to lymphangiogenesis signaling, and these findings point toward the YTHDF2-RNF43-WNT5B pathway as a subject of interest for future therapeutic exploration in OSCC.