Abstract
BackgroundGliomas are the most common malignant primary brain tumours with a highly immunosuppressive tumour microenvironment (TME) and poor prognosis. Circular RNAs (circRNA), a newly found type of endogenous noncoding RNA, characterized by high stability, abundance, conservation, have been shown to play an important role in the pathophysiological processes and TME remodelling of various tumours.MethodsCircRNA sequencing analysis was performed to explore circRNA expression profiles in normal and glioma tissues. The biological function of a novel circRNA, namely, circNEIL3, in glioma development was confirmed both in vitro and in vivo. Mechanistically, RNA pull-down, mass spectrum, RNA immunoprecipitation (RIP), luciferase reporter, and co-immunoprecipitation assays were conducted.ResultsWe identified circNEIL3, which could be cyclized by EWS RNA-binding protein 1(EWSR1), to be upregulated in glioma tissues and to correlate positively with glioma malignant progression. Functionally, we confirmed that circNEIL3 promotes tumorigenesis and carcinogenic progression of glioma in vitro and in vivo. Mechanistically, circNEIL3 stabilizes IGF2BP3 (insulin-like growth factor 2 mRNA binding protein 3) protein, a known oncogenic protein, by preventing HECTD4-mediated ubiquitination. Moreover, circNEIL3 overexpression glioma cells drives macrophage infiltration into the tumour microenvironment (TME). Finally, circNEIL3 is packaged into exosomes by hnRNPA2B1 and transmitted to infiltrated tumour associated macrophages (TAMs), enabling them to acquire immunosuppressive properties by stabilizing IGF2BP3 and in turn promoting glioma progression.ConclusionsThis work reveals that circNEIL3 plays a nonnegligible multifaceted role in promoting gliomagenesis, malignant progression and macrophage tumour-promoting phenotypes polarization, highlighting that circNEIL3 is a potential prognostic biomarker and therapeutic target in glioma.
Highlights
Gliomas are the most common malignant primary brain tumours with a highly immunosuppressive tumour microenvironment (TME) and poor prognosis
CircNEIL3 was significantly upregulated in glioma tissues To identify potential oncogenic Circular RNAs (circRNA) involved in the tumorigenesis and progression of glioma, we analysed the expression profiles of circRNAs in 39 glioma tissues (11 Glioblastoma multiforme (GBM) cases and 28 low-grade glioma (LGG) cases) and 8 normal brain tissues (NBTs) using RNA sequencing (RNA-seq)
CircNEIL3 was markedly upregulated in glioma tissues compared with NBTs, and its expression increased with the increasing glioma grade (Fig. 1D)
Summary
Gliomas are the most common malignant primary brain tumours with a highly immunosuppressive tumour microenvironment (TME) and poor prognosis. Circular RNAs (circRNA), a newly found type of endogenous noncoding RNA, characterized by high stability, abundance, conservation, have been shown to play an important role in the pathophysiological processes and TME remodelling of various tumours. Glioma is the most common and aggressive primary malignancy of the central nervous system and has a poor prognosis. Circular RNAs (circRNAs), a special class of noncoding RNAs, do not have a 5′ end cap or a 3′ end poly(A) tail; rather, they form a circular structure by covalent bonds and are characterized by high stability, abundance, and conservation [5, 6]. Mounting evidence has shown that circRNAs play key roles in various types of cancers [7, 8], including glioma [9, 10]. There are a large number of circRNAs that appear capable of regulating gliomagenesis, the function of a handful of others remains to be determined
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