Molecular Cancer Li Gang/Xue Hao of Shandong University discover new potential therapeutic targets for glioma

iNature gliomas are the most common malignant primary brain tumors with a highly immunosuppressive tumor microenvironment (TME) and poor prognosis
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Circular RNA (circRNA) is a newly discovered endogenous non-coding RNA with high stability, abundance and conservation, which has been shown to play a role in the pathophysiological process and TME remodeling of various tumors.
important role
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On January 14, 2022, Shandong University Li Gang and Xue Hao jointly published a research paper entitled "EWSR1-induced circNEIL3 promotes glioma progression and exosome-mediated macrophage immunosuppressive polarization via stabilizing IGF2BP3" in Molecular Cancer (IF=27), This study performed circRNA sequencing analysis to explore circRNA expression profiles in normal and glioma tissues
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This study identifies circNEIL3, which can be cyclized by EWS RNA-binding protein 1 (EWSR1), is upregulated in glioma tissues and positively correlates with glioma malignant progression
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Functionally, this study confirmed that circNEIL3 promoted glioma tumorigenesis and oncogenic progression in vitro and in vivo
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Mechanistically, circNEIL3 stabilizes the known oncogenic IGF2BP3 protein by preventing HECTD4-mediated ubiquitination
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Furthermore, circNEIL3-overexpressing glioma cells drive macrophage infiltration into the tumor microenvironment (TME)
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Finally, circNEIL3 was packaged into exosomes by hnRNPA2B1 and delivered to infiltrating tumor-associated macrophages (TAMs), enabling them to acquire immunosuppressive properties by stabilizing IGF2BP3, thereby promoting glioma progression
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In conclusion, this work reveals that circNEIL3 plays a non-negligible multifaceted role in promoting gliomagenesis, malignant progression and macrophage tumor-promoting phenotype polarization, emphasizing that circNEIL3 is a potential prognostic biomarker in glioma.
and therapeutic targets
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Gliomas are the most common and aggressive primary malignant tumors of the central nervous system with poor prognosis
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Glioblastoma multiforme (GBM) is a type of brain glioma, WHO grade IV, the highest degree of malignancy
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Even with active surgery combined with chemoradiotherapy, the therapeutic effect of glioma is still poor
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Therefore, elucidating the molecular mechanisms of glioma progression is of great significance for improving patient prognosis
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Circular RNAs (circRNAs) are a special class of non-coding RNAs without 5' end caps or 3' end poly(A) tails; instead, they form circular structures through covalent bonds, with high stability, abundance, and Conservative features
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Growing evidence suggests that circRNAs play critical roles in various cancers including gliomas
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Although a large number of circRNAs appear to regulate gliomagenesis, a few other functions remain to be determined
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The effects of aberrant glioma-associated signaling are not limited to cancer cells, but extend to a complex network of interactions with the tumor microenvironment (TME)
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The function and composition of the glioma TME are influenced by cancer cell intrinsic signaling pathways and secreted factors
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In turn, cells in the TME can maintain cancer hallmarks by modulating multiple tumor biological properties, including cell proliferation, survival, migration, and immune escape
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In the glioma microenvironment, tumor-associated macrophages (TAMs) composed of bone marrow-derived macrophages (BMDMs) and brain-resident microglia (MG) constitute the most abundant cells in the glioma TME cluster and has been revealed to be a key cellular component of glioma initiation and malignant progression
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Schematic diagram of the article (pictured from Molecular Cancer) Multiple studies have shown that exosomes (50–1150 nm) derived from multivesicular bodies (MVB) contain proteins, lipids, and nucleic acids, such as miRNA, lncRNA, and circRNA, which can serve as Signal carriers perform multiple functions in the interaction between glioma cells and TME cells
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Accumulating evidence suggests that circRNAs are involved in the multifaceted regulation of the TME
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However, until now, details on the mechanism by which circRNAs in exosomes regulate TAM in gliomas have remained elusive
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Understanding these multifaceted communications between gliomas and TAMs could open up new avenues for therapy
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In this study, by analyzing the expression profiles of circRNAs in glioma tissues, a circRNA derived from NEIL3, hsa_circ_0001460, was identified and named circNEIL3
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The expression of circNEIL3, regulated by EWS RNA-binding protein 1 (EWSR1), increased with glioma grade
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Functionally, this study confirmed that circNEIL3 promotes tumorigenesis and glioma progression in vitro and in vivo
.

Mechanistically, circNEIL3 stabilizes the known oncogenic IGF2BP3 protein by preventing HECTD4-mediated ubiquitination
.

Furthermore, circNEIL3-overexpressing glioma cells drive macrophage infiltration into the TME by activating YAP1 signaling and secreting CCL2 and LOX, which are potent macrophage chemokines
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Finally, circNEIL3 can be packaged into exosomes via hnRNPA2B1 and delivered to infiltrating TAMs, enabling them to acquire immunosuppressive properties by stabilizing IGF2BP3, thereby promoting glioma progression
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Therefore, our data provide evidence that circNEIL3 may serve as a potential prognostic biomarker and therapeutic target in glioma
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 Reference message: https://molecular-cancer.
biomedcentral.
com/articles/10.
1186/s12943-021-01485-6