METTL3-mediated maturation of miR-126-5p promotes ovarian cancer progression via PTEN-mediated PI3K/Akt/mTOR pathway

Methyltransferase-like 3 (METTL3) functions as an RNA methyltransferase that controls the modification of N(6)-methyladenosine (m6A) to influence the biosynthesis, decay, and translation of mRNAs. This study aims to investigate the regulation of METTL3-mediated promotion of microRNA-126-5p (miR-126-5p) in the progression of ovarian Cancer and to identify the mechanisms in relation to Phosphatase and tensin homolog (PTEN) and the PI3K/Akt/mTOR pathway. We found high expression of miR-126-5p in ovarian Cancer samples compared to paired adjacent samples, and also in ovarian Cancer cell lines. Gain-of-function experiments demonstrated that overexpression of miR-126-5p promoted ovarian Cancer cell proliferation, migration, and invasion, and inhibited their Apoptosis. Luciferase reporter assay identified that miR-126-5p could directly bind to PTEN. By targeting PTEN, miR-126-5p could activate the PI3K/Akt/mTOR pathway. Furthermore, the RNA methyltransferase METTL3 promoted the maturation of miR-126-5p via the m6A modification of pri-miR-126-5p. Finally, in vitro and in vivo experiments substantiated that silencing of METTL3 impeded the progression and tumorigenesis of ovarian Cancer by impairing the miR-126-5p-targeted inhibition of PTEN and thus blocking the PI3K/Akt/mTOR pathway. Coherently, knockdown of METTL3 inhibited the effect of miR-126-5p to upregulate PTEN, and thus prevents PI3K/Akt/mTOR pathway activation, thereby suppressing the development of ovarian Cancer. These findings highlight potential targets for the future ovarian Cancer treatment as well as tumorigenic mechanisms mediated by m6A modification.