Hypoxic Glioma Stem Cell–Derived Exosomes Containing Linc01060 Promote Progression of Glioma by Regulating the MZF1/c-Myc/HIF1α Axis

Abstract

Glioma stem cells (GSC) are a subpopulation of tumor cells with special abilities to proliferate and differentiate in gliomas. They are one of the main causes of tumor recurrence, especially under hypoxic conditions. Although long noncoding RNAs (lncRNA) are known to be involved in numerous biological processes and are implied in the occurrence of certain diseases, their role in tumor development and progression remains poorly understood. Here we explored the mechanisms by which lncRNA derived from hypoxic GSCs (H-GSC) cause glioma progression. Isolation and identification of the Linc01060 gene, the exosomes containing them, and the proteins from tumor cells regulating the gene allowed for studying the effects of Linc01060 on proliferation and glycometabolism. H-GSC exerted their effects by transferring exosomes to glioma cells, resulting in a significant increase in Linc01060 levels. Mechanistically, Linc01060 directly interacted with the transcription factor myeloid zinc finger 1 (MZF1) and enhanced its stability. Linc01060 facilitated nuclear translocation of MZF1 and promoted MZF1-mediated c-Myc transcriptional activities. In addition, c-Myc enhanced the accumulation of the hypoxia-inducible factor-1 alpha (HIF1a) at the posttranscriptional level. HIF1a bound the hormone response elements of the Linc01060 promoter, upregulating the transcription of Linc01060 gene. Clinically, Linc01060 was upregulated in glioma and was significantly correlated with tumor grade and poor clinical prognosis. Overall, these data show that secretion of Linc01060-containing exosomes from H-GSCs activates prooncogenic signaling pathways in glioma cells to promote disease progression.Significance: These findings suggest that inhibition of Linc01060containing exosomes or targeting the Linc01060/MZF1/c-Myc/ HIF1a axis may be an effective therapeutic strategy in glioma.

Hypoxia-Related lncRNA Correlates With Prognosis and Immune Microenvironment in Lower-Grade Glioma

“…Hypoxia and lncRNA have been implicated to be critical factors to promote the progression of glioma ( 27 , 28 ). In our study, we identified 340 HRLs and constructed a novel risk signature composed of 19 HRLs.…”

A Hypoxia-related LncRNA Signature Predicts Survival of Primary Lower-grade glioma

“…[30] In gliomas, Li et al found Linc01060 was upregulated in glioma and was signi cantly correlated with tumor grade and poor clinical prognosis. [31] Linc01060 activates prooncogenic signaling pathways in glioma cells to promote tumor progression. Mineo et al found that HIF1A-AS2 was upregulated in mesenchymal glioblastoma stem-like cell and facilitated the maintenance of mesenchymal glioblastoma stem-like cells in hypoxic niches.…”

Roles of Long Noncoding RNAs in Conferring Glioma Progression and Treatment

“…These researchers constructed a prognostic risk signature with 6 lncRNAs in LGG, and this research illustrated that AL031722.1 and LINC00844 decreased when the risk score was increased, while the expression of AL354740.1, FGD5-AS1, and NEAT1 increased (50). The team of Li et al indicated that the expression of LINC01060 was upregulated in glioma and significantly related to tumor grade and poor clinical prognosis (51). Furthermore, Liu et al revealed that the level of RMST was related to histological grade, and 95.6% of HGGs had higher RMST expression (52).…”