miR-139/PDE2A-Notch1 feedback circuit represses stemness of gliomas by inhibiting Wnt/β-catenin signaling

Abstract

Rationale:The malignant phenotypes of glioblastomas (GBMs) are primarily attributed to glioma stem cells (GSCs). Our previous study and other reports have suggested that both miR-139 and its host gene PDE2A are putative antitumor genes in various cancers. The aim of this study was to investigate the roles and mechanisms of miR-139/PDE2A in GSC modulation. Methods: Clinical samples were used to determine miR-139/PDE2A expression. Patient-derived glioma stem-like cells (PD-GSCs) were stimulated for immunofluorescent staining, sphere formation assays and orthotopic GBM xenograft models. Bioinformatic analysis and further in vitro experiments demonstrated the downstream molecular mechanisms of miR-139 and PDE2A. OX26/CTX-conjugated PEGylated liposome (OCP) was constructed to deliver miR-139 or PDE2A into glioma tissue specifically. Results: We demonstrated that miR-139 was concomitantly transcribed with its host gene PDE2A. Both PDE2A and miR-139 indicated better prognosis of gliomas and were inversely correlated with GSC stemness. PDE2A or miR-139 overexpression suppressed the stemness of PD-GSCs. FZD3 and β-catenin, which induced Wnt/β-catenin signaling activation, were identified as targets of miR-139 and mediated the effects of miR-139 on GSCs. Meanwhile, PDE2A suppressed Wnt/β-catenin signaling by inhibiting cAMP accumulation and GSK-3β phosphorylation, thereby modulating the self-renewal of PD-GSCs. Notably, Notch1, which is also a target of miR-139, suppressed PDE2A/miR-139 expression directly via downstream Hes1, indicating that miR-139 promoted its own expression by the miR-139-Notch1/Hes1 feedback circuit. Expectedly, targeted overexpression miR-139 or PDE2A in glioma with OCP system significantly repressed the stemness and decelerated glioma progression. Conclusions: Our findings elaborate on the inhibitory functions of PDE2A and miR-139 on GSC stemness and tumorigenesis, which may provide new prognostic markers and therapeutic targets for GBMs.

Systems Medicine for Precise Targeting of Glioblastoma

“…He et al concluded that miR-210-3p can inhibit glioma growth, migration, and proliferation by targeting the iron–sulfur cluster assembly protein (Iscu) gene in mouse models [ 83 ]. Another group suggested that overexpression of miR-139 exercises a tumor suppressive effect by inhibiting the stemness GSCs [ 84 ]. The miR-146a suppresses gliomas, whereas the knockdown of miR-146a by miR sponge upregulates Notch1 and promotes tumorigenesis of malignant astrocytes which induce the miR-146a as a negative-feedback mechanism to restrict tumor growth by suppressing Notch1 [ 85 ].…”

MicroRNA-139, an Emerging Gate-Keeper in Various Types of Cancer

“…Multiple well-known oncogenes silence the expression of MIR139 in cancer. For instance, NOTCH1 signaling suppresses MIR139 expression via the transcriptional repressor HES1, which binds to the E-box site at position +644 bp in the PDE2A gene in glioma cells ( Figure 2 B) [ 67 ]. In this study, the authors show that miR-139 modulates stemness by inhibiting Wnt/β-catenin signaling, which is a hallmark of cancer [ 67 ].…”

“…For instance, NOTCH1 signaling suppresses MIR139 expression via the transcriptional repressor HES1, which binds to the E-box site at position +644 bp in the PDE2A gene in glioma cells ( Figure 2 B) [ 67 ]. In this study, the authors show that miR-139 modulates stemness by inhibiting Wnt/β-catenin signaling, which is a hallmark of cancer [ 67 ]. As NOTCH1 is a direct target of miR-139 (discussed below), this creates a feedback mechanism that fine-tunes NOTCH1 signaling ( Figure 2 B).…”

Non-coding RNAs and glioma: Focus on cancer stem cells

“… 345 miR-139 miRNA inhibitory functions on GSC stemness and tumorigenesis inhibiting Wnt/β-catenin signalling Li et al. 202 miR-27a-5p miRNA enhanced the sensitivity of glioma stem cells to radiotherapy shFOSL1-inhibited miR-27a-5p expression Li et al. 346 miR-944 miRNA reduces glioma growth and angiogenesis inhibiting AKT/ERK signalling Jiang et al.…”