Hypoxic Glioma Stem Cell-Derived Exosomes Containing Linc01060 Promote Progression of Glioma by Regulating the MZE1/c-Myc/HIF1α Axis

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 he 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 MZE1 and promoted MZE1-mediated c-Myc transcriptional activities. In addition, c-Myc enhanced the accumulation of the hypoxia-inducible factor-1 alpha (HIF1 alpha) at the posttranscriptional level. HIF1 alpha 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 Linc01060-containing exosomes or targeting the Linc01060/MZEI/c-Myc/HIF1 alpha axis may be an effective therapeutic strategy in glioma.

Automated summary

The study elucidated the mechanisms by which hypoxic lncRNA derived from glioma stem cells (GSC) drive glioma progression, involving the Linc01060 gene, exosomes containing it, and proteins regulating the gene. Transfer of exosomes from GSCs to glioma cells increased Linc01060 levels and activated prooncogenic signaling pathways. Inhibition of Linc01060-containing exosomes or targeting the Linc01060/MZEI/c-Myc/HIF1 alpha axis could be an effective therapeutic strategy in glioma.