MiR-146b-5p suppresses glioblastoma cell resistance to temozolomide through targeting TRAF6

Abstract

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 miR-146b-5p promotes glioma cell proliferation, reduces apoptosis, and correlates with poor survival of patients. Nonetheless, the function of miR-146b-5p in temozolomide resistance remains unclear. In the present study, we successfully generated U87 and U251-TR cells, and found that miR-146b-5p was downregulated in TR cells. Overexpression of miR-146b-5p restored sensitivity of U87/U251-TR cells to TMZ by targeting tumor necrosis factor receptor-associated factor 6 (TRAF6). The levels of TRAF6 were inversely related to miR-146b-5p levels, and overexpression of TRAF6 in miR-146b-5p-OE 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 miR-146b-5p or TRAF6 knockdown significantly decreased the level of p-AKT and p-p65. Collectively, our data demonstrated that miR-146b-5p, as a tumor suppressor, mediated temozolomide resistance in GBM cells through negatively regulating TRAF6 expression, indicating that miR-146b-5p and its targeted genes would be potential therapeutic targets for glioma therapy.