CircRNAs are a class of single-stranded RNA molecules with a covalently closed loop structure and have been characterized by high stability, abundance, conservation, and display tissue/developmental stage-specific expression, furthermore, based on the abundance in distinct body fluids or exosomes, circRNAs present novel biomarkers and targets for the diagnosis and prognosis of cancers. Recently, the regulatory mechanisms of biogenesis and molecular functions, including miRNAs and RBPs sponge, translation as well as transcriptional and splicing regulation, have been gradually uncovered, although various aspects remained to be elucidated in combination with deep-sequence and bioinformatics. Accumulating studies have indicated that circRNAs are more enriched in neuronal tissues partly due to the abundance of specific genes promoting circularization, suggesting dysregulation of circRNAs is closely related to diseases of the nervous system, including glioma. In this review, we elaborate on the biogenesis, functions, databases as well as novel advances especially involved in the molecular pathways, highlight its great value as diagnostic or therapeutic targets in glioma.
Accumulating evidence indicates that the dysregulation of the miRNAs/mRNA-mediated carcinogenic signaling pathway network is intimately involved in glioma initiation and progression. In the present study, by performing experiments and bioinformatics analysis, we found that RPN2 was markedly elevated in glioma specimens compared with normal controls, and its upregulation was significantly linked to WHO grade and poor prognosis. Knockdown of RPN2 inhibited tumor proliferation and invasion, promoted apoptosis, and enhanced temozolomide (TMZ) sensitivity in vitro and in vivo. Mechanistic investigation revealed that RPN2 deletion repressed β-catenin/Tcf-4 transcription activity partly through functional activation of glycogen synthase kinase-3β (GSK-3β). Furthermore, we showed that RPN2 is a direct functional target of miR-181c. Ectopic miR-181c expression suppressed β-catenin/Tcf-4 activity, while restoration of RPN2 partly reversed this inhibitory effect mediated by miR-181c, implying a molecular mechanism in which TMZ sensitivity is mediated by miR-181c. Taken together, our data revealed a new miR-181c/RPN2/wnt/β-catenin signaling axis that plays significant roles in glioma tumorigenesis and TMZ resistance, and it represents a potential therapeutic target, especially in GBM.
RUNX3 plays a pivotal role in glioma initiation and progression as a tumor suppressor via attenuation of Wnt signaling, highlighting it as a potential therapeutic target for glioma.
Accumulating data demonstrates that the network dysregulation of microRNA-medicated target genes is involved in glioma. We have previously found miR-19a/b overexpression in glioma cell lines and specimens with various tumour grades. However, there was no report on the function and regulatory mechanism of miR-19a/b in glioma. In this study, based on our previous research data, we first determine the inverse relationship between miR-19 (miR-19a and miR-19b) and RUNX3 which is also identified the reduced expression in tumour tissues by real-time PCR and IHC. Luciferase reporter assay and western blot analysis revealed that RUNX3 was a direct target of miR-19. Down-regulation of miR-19 dramatically inhibited proliferation, invasion and induced the cell cycle G1 arrest and apoptosis, at least partly via the up-regulation of RUNX3. Furthermore, Mechanistic investigation indicated that knockdown of miR-19 repressed the β-catenin/TCF4 transcription activity. In conclusion, our study validates a pathogenetic role of miR-19 in glioma and establishes a potentially regulatory and signaling involving miR-19 /RUNX3/β-catenin, also suggesting miR-19 may be a candidate therapeutic target in glioma.
11C-PD153035, a potent and specific ATP-competitive tyrosine kinase inhibitor (TKI) of the EGF receptor, has been developed for PET imaging of epidermal growth factor receptor (EGFR) in lung cancer. The objective of the present study was to investigate the relationship of the accumulation of 11C-PD153035 and the EGFR expression level in human gliomas and to explore whether 11C-PD153035 can be used in the molecular imaging of glioma with EGFR overexpression. Eleven patients with histopathologically proven gliomas underwent 11C-PD153035 PET/CT examination before surgery. Combining MRI with the 11C-PD153035 PET/CT image, 2 specimens from different C-PD153035 uptake regions of each tumor and adjacent normal brain tissue were selected as the biopsy targets through the stereotactic technique. The radioactivity concentrations were analyzed as the mathematical maximum standardized uptake value (SUVmax) in region of interest (ROI). The EGFR expression in the biopsied tissues was analyzed by immunohistochemical staining (IHC) and western blotting. The SUVmax/WM (11C-PD153035 uptake in the white matter of the contralateral normal hemisphere) ratio was used to indicate the EGFR expression level in the ROI in PET/CT, and it was correlated with the EGFR expression detected by IHC and western blot analysis. The results demonstrated that 6 of the 8 patients with glioblastoma (GBM) were obviously visualized by 11C-PD153035 PET/CT, whereas 2 patients with GBM, 1 with anaplastic astrocytoma, and 2 with oligodendroglioma did not show significant 11C-PD153035 uptake. There were positive correlations between the SUVmax/WM and the results of IHC (r = 0.955, P< 0.01) and western blotting(r = 0.889, P < 0.010). Our preliminary findings suggest that 11C-PD153035 PET/CT is a promising method for the EGFR-targeted molecular imaging of human GBM, which may be translated into the clinic to select the appropriate population of patients for EGFR-targeted therapy and to assess the early targeted therapeutic response of malignant gliomas.
MicroRNAs (miRs), which act as crucial regulators of oncogenes and tumor suppressors, have been confirmed to play a significant role in the initiation and progression of various malignancies, including glioma. The present study analyzed the expression and roles of miR-422a in glioma, and reverse transcription-quantitative PCR confirmed that miR-422a expression was significantly lower in glioblastoma multiforme (GBM) samples and cell lines compared with the low-grade glioma samples and the H4 cell line, respectively. miR-422a overexpression suppressed proliferation and invasion, and induced apoptosis in LN229 and U87 cell lines. Luciferase reporter assay, western blotting and RNA immunoprecipitation analysis revealed that ribophorin II (RPN2) is a direct functional target of miR-422a. Additionally, the overexpression of RPN2 partially reversed the miR-422a-mediated inhibitory effect on the malignant phenotype. Mechanistic investigation demonstrated that the upregulation of miR-422a inhibited β-catenin/transcription factor 4 transcriptional activity, at least partially through RPN2, as indicated by in vitro and in vivo experiments. Furthermore, RPN2 expression was inversely correlated with miR-422a expression in GBM specimens and predicted patient survival in the Chinese Glioma Genome Atlas, UALCAN, Gene Expression Profiling Interactive Analysis databases. In conclusion, the present data reveal a new miR-422a/RPN2/Wnt/β-catenin signaling axis that plays critical roles in glioma tumorigenesis, and it represents a potential therapeutic target for GBM.
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