Abstract
Robust proliferation and apoptosis inhibition of tumor cells are responsible for the high mortality and poor outcome of patients with high-grade gliomas. miR-29a/b/c have been reported to be important suppressors in several human tumor types. However, their exact roles in gliomagenesis and their relevance to patient prognosis remain unclear. In this study, using 187 human glioma specimens and 20 nontumoral brain tissues, we demonstrated that the expression of miR-29a/b/c decreased progressively as the grade of glioma and the Ki-67 index increased. However, the expression of TRAF4, the functional target of miR-29a/b/c, exhibited the inverse trend, and its level was inversely correlated with the levels of miR-29a/b/c. A Kaplan-Meier analysis demonstrated that the miR-29a/b/c and TRAF4 levels were closely associated with patient survival even in patients with the same tumor grade and identical IDH gene status. A functional study verified that miR-29a/b/c induced apoptosis and suppressed the proliferation of glioma cells by directly targeting TRAF4. An investigation of the mechanism revealed that miR-29a/b/c promoted apoptosis through the TRAF4/AKT/MDM2 pathway in a p53-dependent manner, while miR-29a/b/c induced G1 arrest and inhibited tumor cell proliferation by blocking the phosphorylation of AKT and GSK-3β, and the expression of cyclin D1 and c-Myc. Furthermore, TRAF4-knockdown perfectly simulated the anti-glioma effects of miR-29a/b/c. These findings enrich our understanding of gliomagenesis, highlight the prognostic value of miR-29a/b/c and TRAF4, and imply their potential therapeutic roles in malignant gliomas.