METTL3-Mediated m6A Modification of FYN: Regulating Tumor-Associated Endothelial Cells in Colorectal Cancer Progression.

BACKGROUND AND OBJECTIVE: Colorectal cancer (CRC) presents complex challenges in treatment and prognosis. This study aims to elucidate the role and mechanism of FYN in colorectal cancer progression and its potential as a prognostic marker.

METHODS: The expression of FYN in colorectal cancer and adjacent tissues was assessed using qPCR and Western blot analyses, complemented by data from The Human Protein Atlas and Kaplan-Meier Plotter databases. The regulatory effects of FYN on Slit2 expression via the mTOR pathway were explored through genetic manipulation in various colorectal cancer cell lines. Additionally, the impact of FYN expression on properties of tumor-associated endothelial cells (TAECs) was investigated through co-culture experiments. The m6A methylation modulated FYN expression was evaluated by analyzing the effect of METTL3 on FYN mRNA stability.

RESULTS: FYN was significantly upregulated in colorectal cancer tissues, correlating positively with tumor size, stage, and metastasis. High FYN expression was associated with poor survival outcomes. Regulatory effects of FYN on Slit2 expression via the mTOR pathway were evident. Enhanced FYN expression facilitated endothelial-to-mesenchymal transition (EndMT), angiogenesis, and compromised barrier function in TAECs. METTL3 was found to stabilize FYN mRNA through m6A methylation, influencing FYN expression and downstream effects on Slit2 via the mTOR pathway.

CONCLUSION: FYN plays a crucial role in colorectal cancer progression, influencing tumor growth, metastasis, and patient prognosis through the regulation of Slit2 expression and TAECs properties. METTL3-mediated m6A methylation of FYN mRNA is a key mechanism in maintaining FYN stability, suggesting potential therapeutic targets in colorectal cancer treatment.