GAS5 suppresses malignancy of human glioma stem cells via a miR-196a-5p/FOXO1 feedback loop

摘要

Abstract Glioma stem cells (GSCs) make up highly tumorigenic subpopulations within gliomas, and aberrant expression of GSC genes is a major underlying cause of glioma pathogenesis and treatment failure. The present study characterized the expression and function of long non-coding RNA growth arrest specific 5 (GAS5) in GSCs in order to elucidate the molecular mechanisms by which GAS5 contributes to glioma pathogenesis. We demonstrate that GAS5 suppresses GSC malignancy by binding to miR-196a-5p. miR-196a-5p, an onco-miRNA, stimulates GSC proliferation, migration, and invasion, in addition to reducing levels of apoptosis. miR-196a-5p specifically downregulates the expression of forkhead box protein O1 (FOXO1) by targeting its 3′ untranslated region (3′-UTR). FOXO1 upregulates expression of phosphotyrosine interaction domain containing 1 (PID1), thereby inhibiting GSC tumorigenicity and growth. FOXO1 also upregulates migration and invasion inhibitory protein (MIIP), resulting in attenuation of migration and invasion activities. Interestingly, we also show that FOXO1 promotes GAS5 transcription, thus forminga positive feedback loop. These data provide insights into potential new pathways for GSC molecular therapy and suggest that GAS5 may be an efficacious target for glioma treatments. Highlights ? LncRNA GAS5 is lowly expressed and it is a tumor-suppressive factor in human glioma stem cells (GSCs). ? GAS5 binds and down-regulates oncomiRNA-196a-5p. ? miR-196a-5p mediates the malignancy suppression of GAS5 by targeting and inhibiting FOXO1. ? FOXO1 binds to the promoter regions and promotes the transcription of MIIP and PID1. ? FOXO1 promotes the transcription of GAS5 thus forming a positive feedback loop. ]]>