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

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Abstract

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.

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Fig. 1: miR-126-5p is highly expressed in ovarian cancer and this high miR-126-5p expression promotes the growth of ovarian cancer cells and inhibits their apoptosis.
Fig. 2: miR-126-5p inhibits PTEN expression to promote the proliferation, migration, and invasion of ovarian cancer cells and inhibit their apoptosis.
Fig. 3: miR-126-5p activates the PI3K/Akt/mTOR pathway by inhibiting PTEN.
Fig. 4: miR-126-5p promotes ovarian cancer progression by inhibiting the PTEN-mediated PI3K/Akt/mTOR pathway.
Fig. 5: Methyltransferase METTL3 promotes miR-126-5p expression by mediating the m6A epigenetic modification of pri-miR-126-5p.
Fig. 6: Downregulation of METTL3 suppresses the development of ovarian cancer via the miR-126-5p/PTEN/PI3K/Akt/mTOR axis.
Fig. 7: METTL3 silencing inhibits the xenograft tumor growth in vivo.
Fig. 8: The schematic diagram showing the detailed mechanism of METTL3 in the development of ovarian cancer via regulating the miR-126-5p/PTEN/PI3K/Akt axis.

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Bi, X., Lv, X., Liu, D. et al. METTL3-mediated maturation of miR-126-5p promotes ovarian cancer progression via PTEN-mediated PI3K/Akt/mTOR pathway. Cancer Gene Ther 28, 335–349 (2021). https://doi.org/10.1038/s41417-020-00222-3

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