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

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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."