Tumor Cell-Derived Exosomal METTL3 Induces Choriocarcinoma Malignant Progression by Targeting Fbxw8

Choriocarcinoma (CC) is a highly malignant tumor that occurs in women. Methyltransferase-like 3 (METTL3) is a key protein of m6A methyltransferase complex and its role in CC has been studied, but the study of exosomal METTL3 in CC has not been reported. In this study, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were used to assess the expressions of related genes. Cell counting kit-8 (CCK-8) assay, wound healing assay, transwell assay, and relevant kit assays were employed to detect the behaviors of tumor cells after different treatments. Moreover, exosome-related researches were performed using kits and transmission electron microscope. Online software was applied to predict the relationship between METTL3 and F-box and WD repeat domain containing 8 (Fbxw8), verified by methylated RNA immunoprecipitation (MeRIP)-qPCR. Furthermore, xenograft mouse models were constructed for validation experiments in vivo. METTL3 was overexpressed in CC cell lines, and was a promoter of CC progression and glycolysis. In addition, METTL3 was highly expressed in tumor cell-derived exosomes and decreased with the addition of GW4869, an exosome inhibitor. Similarly, the knockdown of tumor cell-derived METTL3 also inhibited CC progression and glycolysis. Mechanically, tumor cell-derived exosomal METTL3 motivated the malignant progression of CC by mediating m6A methylation and expression of Fbxw8. In vivo, tumor cell-derived exosomal METTL3 also expedited tumor growth through Fbxw8. Tumor cell-derived exosomal METTL3 promotes glycolysis in CC via regulating m6A methylation modification on Fbxw8 mRNA to further amplify tumor malignant progression, and this will provide a new target for the treatment of CC in the future.