CSIG-28. LONG NONCODING RNA MIR22 HOST GENE-DERIVED miR-22-3p AND miR-22-5p PROMOTE PROLIFERATION, INVASION AND SELF-RENEWAL IN HUMAN GLIOMAS VIA Wnt/-CATENIN SIGNALING

BACKGROUND: Long noncoding RNAs (lncRNAs) are essential transcripts with critical roles in tumor initiation and malignant progression. In the present study, through analysis of whole-transcriptome profiles, we showed that MIR22 host gene (MIR22HG), the primary microRNA of miR-22, ranked among the most overexpressed lncRNAs in glioblastoma (GBM). Herein, our study aims to elucidate the biological functions of MIR22HG and therapeutic potency of MIR22HG targeted inhibition in GBM. METHODS: We characterized the expression pattern of MIR22HG/miR-22 by bioinformatics analysis and by in situ hybridization (ISH) in GBMs. We further determined whether genetic targeting of MIR22HG affected oncogenic functions of primary GBM cells in vitro and in vivo. A co-culture model where brain organoids are co-cultured with GBM spheroids were utilized for the invasion assessment. Finally, based on the three-dimensional structure of the pre-miR-22, we performed virtual screening strategy to disclose a novel inhibitor of the MIR22HG/miR-22 axis. RESULTS: We showed that MIR22HG/miR-22 was highly expressed in GBM, especially in isocitrate dehydrogenase 1/2 (IDH1/2) wild-type tumors. Specially, MIR22HG/miR-22 was preferentially expressed in glioblastoma stem cells (GSCs) compared to normal neural stem cell (NSCs). Analysis of intra-tumoral transcriptional heterogeneity showed that MIR22HG was higher in the infiltrating region compared to the tumor center. In functional assays, silencing MIR22HG attenuated aggressive phenotypes in GBM cells, including invasion, self-renewal and in vivo tumor growth via suppressing the production of miR-22-3p and miR-22-5p. Using a luciferase reporter assay, we further confirmed that two inhibitors of the Wnt/β-catenin pathway, SFRP2 and PCDH15, were direct targets of miR-22-3p and miR-22-5p. Finally, we identified a specific inhibitor termed AC1L6JTK, which blocks the ability of Dicer to process pre-miR-22 to mature miR-22, thus exerting therapeutic efficacy on GBMs. CONCLUSIONS: Our findings show that the MIR22HG/miR-22 axis is a novel biomarker as well as a therapeutic target in GBM.