UPF1/circRPPH1/ATF3 feedback loop promotes the malignant phenotype and stemness of GSCs

Glioblastoma multiforme (GBM) is the most lethal type of craniocerebral gliomas. Glioma stem cells (GSCs) are fundamental reasons for the malignancy and recurrence of GBM. Revealing the critical mechanism within GSCs' self-renewal ability is essential. Our study found a novel circular RNA (circRPPH1) that was up-regulated in GSCs and correlated with poor survival. The effect of circRPPH1 on the malignant phenotype and self-renewal of GSCs was detected in vitro and in vivo. Mechanistically, UPF1 can bind to circRPPH1 and maintain its stability. Therefore, more existing circRPPH1 can interact with transcription factor ATF3 to further transcribe UPF1 and Nestin expression. It formed a feedback loop to keep a stable stream for stemness biomarker Nestin to strengthen tumorigenesis of GSCs continually. Besides, ATF3 can activate the TGF-beta signaling to drive GSCs for tumorigenesis. Knocking down the expression of circRPPH1 significantly inhibited the proliferation and clonogenicity of GSCs both in vitro and in vivo. The overexpression of circRPPH1 enhanced the self-renewal of GSCs. Our findings suggest that UPF1/circRPPH1/ATF3 maintains the potential self-renewal of GSCs through interacting with RNA-binding protein and activating the TGF-beta signal pathway. Breaking the feedback loop against self-renewing GSCs may represent a novel therapeutic target in GBM treatment.

Automated summary

This study identified a novel up-regulated circular RNA, circRPPH1, in Glioma stem cells (GSCs), which was associated with poor survival. circRPPH1 promoted the malignant phenotype and self-renewal ability of GSCs. Mechanistically, UPF1 interacted with circRPPH1 to maintain its stability, leading to enhanced interaction between circRPPH1 and transcription factor ATF3 and further transcription of UPF1 and Nestin. This formed a feedback loop resulting in continuous enhancement of tumorigenicity in GSCs through increased Nestin expression. Additionally, ATF3 activated the TGF-beta signaling pathway to drive GSCs tumorigenesis. Knocking down circRPPH1 expression inhibited proliferation and clonogenicity of GSCs, while overexpression of circRPPH1 enhanced self-renewal of GSCs. These findings suggest that the UPF1/circRPPH1/ATF3 pathway maintains the self-renewal ability of GSCs by interacting with RNA-binding protein and activating the TGF-beta signal pathway. Breaking this feedback loop could serve as a novel therapeutic target in GBM treatment.