Abstract
Background
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 long 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 NGS data analysis.
Results
Our results suggest that circMMP9 functions as a sponge for miR-149 and miR-542, both of which show upregulation in GBM based on microarray data analysis. 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, also known as 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 HNRNPC (heterogeneous nuclear ribonucleoprotein C) and HRNPA1 (heterogeneous nuclear ribonucleoprotein A1), although not within their protein-binding domains. This suggests that HNRNPC and HRNPA1 may play a role in transporting circMMP9. Moreover, RNA-seq data from GBM patient samples confirmed the increased expression of BIRC5, PIK3CB, HNRNPC, and HRNPA1, further emphasizing the potential therapeutic significance of circMMP9 in GBM.
Conclusion
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.