Role of Circular RNA MMP9 in Glioblastoma Progression: From Interaction With hnRNPC and hnRNPA1 to Affecting the Expression of BIRC5 by Sequestering miR‐149.

ABSTRACT Glioblastoma multiforme (GBM) presents a significant challenge in neuro‐oncology due to its aggressive behavior and self‐renewal capacity. Circular RNAs (circRNAs), a subset of non‐coding RNAs (ncRNAs) generated through mRNA back‐splicing, are gaining attention as potential targets for GBM research. In our study, we sought to explore the functional role of circMMP9 (circular form of matrix metalloproteinase‐9) as a promising therapeutic target for GBM through bioinformatic predictions and human data analysis. Our results suggest that circMMP9 functions as a sponge for miR‐149 and miR‐542, both upregulated in GBM based on microarray data. Kaplan–Meier analysis indicated that reduced levels of miR‐149 and miR‐542 correlate with worse survival outcomes in GBM, suggesting their role as tumor suppressors. Importantly, miR‐149 has been demonstrated to inhibit the expression of BIRC5 (baculoviral inhibitor of apoptosis repeat‐containing 5 or survivin), a significant promoter of proliferation in GBM. BIRC5 is not only upregulated in GBM but also in various other cancers, including neuroblastoma and other brain cancers. Our protein–protein interaction analysis highlights the significance of BIRC5 as a central hub gene in GBM. CircMMP9 seems to influence this complex relationship by suppressing miR‐149 and miR‐542, despite their increased expression in GBM. Additionally, we found that circMMP9 directly interacts with heterogeneous nuclear ribonucleoproteins C and A1 (hnRNPC and A1), although not within their protein‐binding domains. This suggests that hnRNPC/A1 may play a role in transporting circMMP9. Moreover, RNA‐seq data from GBM patient samples confirmed the increased expression of BIRC5, PIK3CB, and hnRNPC/A1, further emphasizing the potential therapeutic significance of circMMP9 in GBM. In this study, we propose for the first time a new epigenetic regulatory role for circMMP9, highlighting a novel aspect of its oncogenic function. circMMP9 may regulate BIRC5 expression in GBM by sponging miR‐149 and miR‐542. BIRC5, in turn, suppresses apoptosis and enhances proliferation in GBM. Nonetheless, more extensive studies are advised to delve deeper into the roles of circMMP9, especially in the context of glioma. [ABSTRACT FROM AUTHOR]