Amini Javad, Zafarjafarzadeh Nikta, Ghahramanlu Sara, Mohammadalizadeh Omid, Mozaffari Elaheh, Bibak Bahram, Sanadgol Nima
Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran.
Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
J Mol Recognit. 2025 Jan;38(1):e3109. doi: 10.1002/jmr.3109. Epub 2024 Oct 14.
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.
多形性胶质母细胞瘤（GBM）因其侵袭性和自我更新能力，在神经肿瘤学中构成了重大挑战。环状RNA（circRNAs）是通过mRNA反向剪接产生的非编码RNA（ncRNAs）的一个子集，作为GBM研究的潜在靶点正受到关注。在我们的研究中，我们试图通过生物信息学预测和人类数据分析，探索circMMP9（基质金属蛋白酶9的环状形式）作为GBM有前景的治疗靶点的功能作用。我们的结果表明，circMMP9作为miR-149和miR-542的海绵发挥作用，基于微阵列数据，这两种miRNA在GBM中均上调。Kaplan-Meier分析表明，miR-149和miR-542水平降低与GBM患者较差的生存结果相关，表明它们作为肿瘤抑制因子的作用。重要的是，已证明miR-149可抑制BIRC5（含杆状病毒凋亡重复序列5或生存素）的表达，BIRC5是GBM中增殖的重要促进因子。BIRC5不仅在GBM中上调，在包括神经母细胞瘤和其他脑癌在内的各种其他癌症中也上调。我们的蛋白质-蛋白质相互作用分析突出了BIRC5作为GBM中核心枢纽基因的重要性。尽管circMMP9在GBM中表达增加，但它似乎通过抑制miR-149和miR-542来影响这种复杂关系。此外，我们发现circMMP9直接与不均一核核糖核蛋白C和A1（hnRNPC和A1）相互作用，尽管不是在它们的蛋白质结合域内。这表明hnRNPC/A1可能在circMMP9的转运中发挥作用。此外，来自GBM患者样本的RNA测序数据证实了BIRC5、PIK3CB和hnRNPC/A1的表达增加，进一步强调了circMMP9在GBM中的潜在治疗意义。在本研究中，我们首次提出circMMP9具有新的表观遗传调控作用，突出了其致癌功能的一个新方面。circMMP9可能通过充当miR-149和miR-542的海绵来调节GBM中BIRC5的表达。反过来，BIRC5抑制GBM中的细胞凋亡并增强增殖。尽管如此，建议进行更广泛的研究以更深入地探究circMMP9的作用，特别是在胶质瘤的背景下。
