miR-148-3p Inhibits Growth of Glioblastoma Targeting DNA Methyltransferase-1 (DNMT1)

To date, miR-148-3p and DNMT1-recombinant human runt-related transcription factor 3 (RUNX3) axis have been linked to cell proliferation, migration, and invasion; however, their roles and relationships in human glioblastoma multiforme (GBM) are still not clear. Here we found that the expression of miR-148-3p in glioma tissues was decreased compared with adjacent nontumor tissues and correlated with WHO grade, tumor size, and prognosis as well as DNMT1 and RUNX3 expressions. Compared with NHA cells, the expression of miR-148-3p in U87 and U251 cells was also downregulated and accompanied with upregulation of DNMT1 and hypermethylation level of RUNX3 promoter region. miR-148-3p overexpression induced apoptosis and cell cycle arrest of U87 and U251 cells, and affected cell migration and invasion. miR-148-3p mimics effectively suppressed the expression of DNMT1 and methylation of RUNX3 promoter, finally upregulating RUNX3 expression. Mechanistically, the 3-untranslated region (3-UTR) of DNMT1 was a direct target of miR-148-3p. Overexpression of miR-148-3p or inhibition of DNMT1 induced the expression of E-cadherin and reduced the expressions of N-cadherin, vimentin, MMP-2, and MMP-9. In conclusion, miR-148-3p directly repressed the expression of DNMT1 and inhibited proliferation, migration, and invasion by regulating DNMT1-RUNX3 axis and the epithelial-mesenchymal transition in GBM. Our findings provide a new foundation for treatment of patients with GBM.