Kishore Balasubramanian

Introduction. Glioblastoma multiforme (GBM) is one of the most common and fatal primary brain tumors. It is characterized by aggressive proliferation and motility and is highly resistant to conventional radiation and chemotherapy. Research into the dynamic interaction between microenvironment and the biological mechanisms specific to GBM cancer cells is rich with potential in identifying new therapeutic targets and improving treatment. One such area is identifying and targeting micro-RNAs (miRNA) that drive the different hallmarks of cancer. Methods. Four different miRNAs were studied in the context of GBM biology. miR-138, miR-137, miR-376a, and miR-451 to assess cell proliferation, chemoresistance, angiogenesis, and cell migration respectively. Lentivirus transduction was used to ectopically induce miRNA expression, luciferase assay was used to confirm miRNA expression, Transwell/wound healing assay was used to assess cell migration, and CCK8/MTT Assay was used to measure cell viability. PCR and Western blotting were used to determine specific biological mechanisms. Results. miR-376a was downregulated in patient cell lines. Induced expression of miR-376a directly targets and inhibits SIRT1 in glioma cells which in turn decreased YAP1 and VEGF signaling. Overall, this led to suppression of glioma cell proliferation, migration and angiogenesis.¹ miR-451 expression is based on glucose concentration. In glucose + conditions, the cells showed relatively high miR-451 expression, promoting cell growth. In glucose – conditions, miR-451 levels decreased, slowing proliferation but enhancing migration. These effects were mediated through the LKB1/AMPK pathway.² Genomic analysis of patient cell lines showed that cell proliferation was mediated by the downregulation of miR-138. However, transient overexpression of miR-138 in GBM cells inhibited cell proliferation. Molecular studies showed that miR-138 downregulated CD44 expression which led to expression of p27 and cell cycle arrest.³ Finally, chemoresistance was mediated by miR-137. miR-137 was downregulated in GBM samples as compared with normal brain tissues. Induced overexpression of miR-137 inhibited cell invasion and enhanced cell chemosensitivity to temozolomide (TMZ). This effect was mediated through the downregulation of the LRP6 receptor.⁴ Conclusion. Taken together, these results demonstrate the potential in targeting micro RNAs in glioblastoma management and treatment. With the advent of next generation sequencing technologies, micro-RNA based therapies can allow for personalized and effective diagnostics and therapeutics and avoid the systemic toxic effects seen with conventional treatment.

1. Deng, Yong-Wen et al. “miR-376a inhibits glioma proliferation and angiogenesis by regulating YAP1/VEGF signalling via targeting of SIRT1.” Translational oncology vol. 15,1 (2022): 101270. doi:10.1016/j.tranon.2021.101270
2. Godlewski J, Nowicki MO, Bronisz A, et al. MicroRNA-451 regulates LKB1/AMPK signaling and allows adaptation to metabolic stress in glioma cells. Mol Cell. 2010;37(5):620-632. doi:10.1016/j.molcel.2010.02.018
3. Yeh, Margaret et al. “MicroRNA-138 suppresses glioblastoma proliferation through downregulation of CD44.” Scientific reports vol. 11,1 9219. 28 Apr. 2021, doi:10.1038/s41598-021-88615-8
4. Li DM, Chen QD, Wei GN, et al. Hypoxia-Induced miR-137 Inhibition Increased Glioblastoma Multiforme Growth and Chemoresistance Through LRP6. Front Oncol. 2021;10:611699. Published 2021 Feb 25. doi:10.3389/fonc.2020.611699