RESUMEN
Temozolomide (TMZ), as a kind of alkylating agent, is widely utilized for the treatment of glioblastoma (GBM). However, temozolomide resistance (TR) often develops quickly and results in tumor recurrence and poor outcome. Recent advances have demonstrated that miRNAs exert critical roles in chemoresistance. Downregulation of miR146b5p promotes glioma cell proliferation, reduces apoptosis, and correlates with poor survival of patients. Nonetheless, the function of miR146b5p in temozolomide resistance remains unclear. In the present study, we successfully generated U87 and U251TR cells, and found that miR146b5p was downregulated in TR cells. Overexpression of miR146b5p restored sensitivity of U87/U251TR cells to TMZ by targeting tumor necrosis factor receptor-associated factor 6 (TRAF6). The levels of TRAF6 were inversely related to miR146b5p levels, and overexpression of TRAF6 in miR146b5pOE cells enhanced the resistance against TMZ. Moreover, temozolomide-resistant GBM cells had a higher level of phosphorylated protein kinase B (AKT) and P65. Overexpression of miR146b5p or TRAF6 knockdown significantly decreased the level of pAKT and pp65. Collectively, our data demonstrated that miR146b5p, as a tumor suppressor, mediated temozolomide resistance in GBM cells through negatively regulating TRAF6 expression, indicating that miR146b5p and its targeted genes would be potential therapeutic targets for glioma therapy.
