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 ofN(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.

Automated summary

METTL3 promotes the maturation of miR-126-5p through m6A modification, which in turn targets PTEN to activate the PI3K/Akt/mTOR pathway in ovarian cancer progression. This study provides potential targets for future ovarian cancer treatment and reveals tumorigenic mechanisms regulated by m6A modification.