RPN2 is targeted by miR-181c and mediates glioma progression and temozolomide sensitivity via the wnt/β-catenin signaling pathway

Abstract

Accumulating evidence indicates that the dysregulation of the miRNAs/mRNA-mediated carcinogenic signaling pathway network is intimately involved in glioma initiation and progression. In the present study, by performing experiments and bioinformatics analysis, we found that RPN2 was markedly elevated in glioma specimens compared with normal controls, and its upregulation was significantly linked to WHO grade and poor prognosis. Knockdown of RPN2 inhibited tumor proliferation and invasion, promoted apoptosis, and enhanced temozolomide (TMZ) sensitivity in vitro and in vivo. Mechanistic investigation revealed that RPN2 deletion repressed β-catenin/Tcf-4 transcription activity partly through functional activation of glycogen synthase kinase-3β (GSK-3β). Furthermore, we showed that RPN2 is a direct functional target of miR-181c. Ectopic miR-181c expression suppressed β-catenin/Tcf-4 activity, while restoration of RPN2 partly reversed this inhibitory effect mediated by miR-181c, implying a molecular mechanism in which TMZ sensitivity is mediated by miR-181c. Taken together, our data revealed a new miR-181c/RPN2/wnt/β-catenin signaling axis that plays significant roles in glioma tumorigenesis and TMZ resistance, and it represents a potential therapeutic target, especially in GBM.

MicroRNA-361-5p slows down gliomas development through regulating UBR5 to elevate ATMIN protein expression

“…The results revealed that survival rate of gliomas patients in different tumor grades with low UBR5 expression was higher (Fig. 1G ) [ 28 ].…”

CN‐3 increases TMZ sensitivity and induces ROS‐dependent apoptosis and autophagy in TMZ‐resistance glioblastoma

“…P‐gp is a significant molecular biomarker associated with poor prognosis and TMZ resistance in glioma cells. [ 17,18 ] qPCR showed that CN‐3 decreased the levels of MGMT and P‐gp (Figure 8C). A close correlation between NF‐κB p65 and MGMT expression has been reported in drug‐resistant gliomas.…”

“…[ 13,14 ] P‐gp is an ATP‐dependent efflux pump that can induce TMZ efflux, resulting in reduced chemosensitivity. [ 15–18 ] High expression of P‐gp and MGMT in glioblastoma is a major factor leading to TMZ resistance. [ 16,54,59 ] The expression of P‐gp and MGMT proteins is related to the sensitivity of TMZ, and reduction of P‐gp and MGMT protein levels, as a good prognostic factor, is related to a better prognosis in glioblastoma patients.…”

“…[ 13,14 ] P‐gp is an ATP‐dependent efflux pump that can induce drug efflux, resulting in reduced chemosensitivity. [ 15–18 ] Patients overexpressing MGMT and P‐gp fare worse, presumably because of TMZ resistance. [ 12,15–19 ] Therefore, there is an urgent need to develop new and effective chemotherapy drugs for glioblastoma.…”

“…[ 15–18 ] Patients overexpressing MGMT and P‐gp fare worse, presumably because of TMZ resistance. [ 12,15–19 ] Therefore, there is an urgent need to develop new and effective chemotherapy drugs for glioblastoma.…”