Role of Circular RNA in Brain Tumor Development

Abstract

Central nervous system tumors are a leading cause of cancer-related death in children and adults, with medulloblastoma (MB) and glioblastoma (GBM) being the most prevalent malignant brain tumors, respectively. Despite tremendous breakthroughs in neurosurgery, radiation, and chemotherapeutic techniques, cell heterogeneity and various genetic mutations impacting cell cycle control, cell proliferation, apoptosis, and cell invasion result in unwanted resistance to treatment approaches, with a 5-year survival rate of 70-80% for medulloblastoma, and the median survival time for patients with glioblastoma is only 15 months. Developing new medicines and utilizing combination medications may be viewed as excellent techniques for battling MB and GBM. Circular RNAs (circRNAs) can affect cancer-developing processes such as cell proliferation, cell apoptosis, invasion, and chemoresistance in this regard. As a result, several compounds have been introduced as prospective therapeutic targets in the fight against MB and GBM. The current study aims to elucidate the fundamental molecular and cellular mechanisms underlying the pathogenesis of GBM in conjunction with circRNAs. Several mechanisms were examined in detail, including PI3K/Akt/mTOR signaling, Wnt/-catenin signaling, angiogenic processes, and metastatic pathways, in order to provide a comprehensive knowledge of the involvement of circRNAs in the pathophysiology of MB and GBM.

Keywords: brain tumor; circular RNA; diagnosis; ependymoma; glioblastoma; medulloblastoma; miRNA; pituitary adenoma; signaling pathway; treatment.

Figure 1

The function of circRNAs’; miRNA molecular sponging: circRNAs with miRNA binding sites can prevent miRNA from attaching to its target mRNA and hence prevent miRNA from inhibiting the target protein. Regulation of translation: circRNAs to bind to the ribosome in order to regulate translation. RBP sponging: circRNAs with an RBP binding site can regulate protein activity. Protein complex scaffold: circRNAs may serve as protein scaffolds.

Figure 2

CircRNA regulation on medulloblastoma: various circRNAs including circ-UNC13C, circ-BRWD3, circ-CNTN6, circ-CRTAM, circ-MCU, circ-RIMS1-1, circ-FLT31, circ-DGKH, circ-FLT3-2, circ-SPHKAP, circ-GRM1, circ-GABRB2, circ-RIMS1-2, circ-ICA1, circ-GRIK2, circ-ATP8A2, circ-EPHX2, circ- WAC, circ-TENM1, circ-SNORD109A, circ-UNC13C, circ-GRIK2, circ-MAP3K5, circ-CAMKK2, circ-SVEP1, circ-CADPS2, circ-CAMK4-1, and circ-CAMK4-2 are responsible for the downregulation of medulloblastoma growth. Although, various circRNAs including circ-SKA3, circ-DTL, and circ-CASC15 are responsible for the up-regulation of medulloblastoma growth.

Figure 3

CircRNAs responsible for upregulation of glioblastoma growth: A schematic representation of the circRNAs involved in the regulation of glioma cell proliferation, migration, and invasion, among other functions. Numerous known circRNAs operate as miRNA sponges, subsequently increasing the amount of expression of the appropriate target genes. These target genes or proteins further influence downstream factors involved in cancer signaling pathways by functioning as transcription factors or regulatory proteins, as well as through other mechanisms. CircRNAs such as hsa-circ-0046701, circ-UBAP2, circ-PARP4, Hsa-circ-0008344, circ-PITX1, circ-ASAP1, circ-MAPK4, circ-TTBK2, circ-0082374, circ- 0001730, circ-0043278, circ-0000177, circ-0000215, circ-0037655, circ-PIP5K1A, circ-SHKBP1, circ-NT5E, hsa-circ-0067934, circ-HIPK3, circ-MMP9, hsa-circ-0012129, circ-ZNF292, circ-CFH, and circ-NFIX are responsible for the up-regulation of glioblastoma growth through different pathways including those of the Mapks, Wnt/β-catenin, TCF12, PI3K/AKT, SOX4/PI3KCA, and Notch. For example, circ-TTBK2 activates the Mapks signaling pathway through miR-217.

Figure 4

CircRNAs responsible for upregulation of glioblastoma growth: A schematic representation of the circRNAs involved in the regulation of glioma cell proliferation, migration, and invasion, among other functions. Numerous known circRNAs operate as miRNA sponges, subsequently increasing the amount of expression of the appropriate target gene. These target genes or proteins further influence downstream factors involved in cancer signaling pathways by functioning as transcription factors or regulatory proteins, as well as through other mechanisms. CircRNAs such as circ-CDC45, circ-0029426, circ-ENTPD7, circ-FLNA, hsa-circ-0076248, circ-0006168, circ-ABCC3, circ-LGMN, circ-FOXO3, hsa-circ-0005114, circ-0074027, circ-SKA3, circ-0001801, Circ-FOXM1, circ-NF1, circ-MELK, circ-NUP98, circ-ATXN1, circ-ARF1, circ-RFX3, and circ-PIK3C2A are responsible for the up-regulation of glioblastoma growth through different pathways including those of the IGF1R/Ras/Erk, Wnt/β-catenin, MMP2/VEGFA, PI3K/AKT, and FOXM1. For example, circ-RFX3 activates the Wnt/β-catenin pathway through miR-587.

Figure 5

CircRNAs that downregulate glioblastoma growth: A schematic representation of the circRNAs involved in the regulation of glioma cell proliferation, migration, and invasion, among other functions. Numerous discovered circRNAs operate as miRNA sponges, therefore downregulating the amount of expression of the relevant target gene. These target genes or proteins further influence downstream factors involved in cancer signaling pathways by functioning as transcription factors, regulatory proteins. CircRNAs such as circ-CDC45, circ- 0029426, circ-ENTPD7, circ-FLNA, hsa-circ- 0076248, circ-0006168, circ-ABCC3, circ-LGMN, Circ-FOXO3, Hsa-circ- 0005114, Circ- 0074027, Circ-SKA3, Circ-0001801, Circ-FOXM1, Circ-NF1, Circ-MELK, Circ-NUP98, circ-ATXN1, circ-ARF1, circ-RFX3, and circ-PIK3C2A are responsible for the down-regulation of glioblastoma growth through different pathways including those of the VEGFA, Wnt/β-catenin, CDR1, PI3K/AKT, WWOX, and SMAD6 pathways. For example, cir-ITCH promotes the Wnt/-catenin signaling pathway via miR-214.