A diagnostic circulating miRNA signature as orchestrator of cell invasion via TKS4/TKS5/EFHD2 modulation in human gliomas

Abstract

Background Altered microRNA profiles have been observed not only in tumour tissues but also in biofluids, where they circulate in a stable form thus representing interesting biomarker candidates. This study aimed to identify a microRNA signature as a non-invasive biomarker and to investigate its impact on glioma biology. Methods MicroRNAs were selected using a global expression profile in preoperative serum samples from 37 glioma patients. Comparison between serum samples from age and gender-matched controls was performed by using the droplet digital PCR. The ROC curve and Kaplan-Meier survival analyses were used to evaluate the diagnostic/prognostic values. The functional role of the identified signature was assessed by gain/loss of function strategies in glioma cells. Results A three-microRNA signature (miR-1-3p/−26a-1-3p/−487b-3p) was differentially expressed in the serum of patients according to the isocitrate dehydrogenase (IDH) genes mutation status and correlated with both patient Overall and Progression Free Survival. The identified signature was also downregulated in the serum of patients compared to controls. Consistent with these results, the signature expression and release in the conditioned medium of glioma cells was lower in IDH-wild type cells compared to the mutated counterpart. Furthermore, in silico analysis of glioma datasets showed a consistent deregulation of the signature according to the IDH mutation status in glioma tumour tissues. Ectopic expression of the signature negatively affects several glioma functions. Notably, it impacts the glioma invasive phenotype by directly targeting the invadopodia-related proteins TKS4, TKS5 and EFHD2. Conclusions We identified a three microRNA signature as a promising complementary or even an independent non-invasive diagnostic/prognostic biomarker. The signature displays oncosuppressive functions in glioma cells and impacts on proteins crucial for migration and invasion, providing potential targets for therapeutic intervention.

The potential of miRNA-based approaches in glioblastoma: An update in current advances and future perspectives

“… ROC curve analysis showed that serum miR-145–5p could effectively distinguish GBM patients from the control groups. Multivariate analysis confirmed that serum miR-145–5p expression was an independent prognostic indicator for overall survival in GBM patients Díaz Méndez et al ( Diaz Mendez et al, 2023 ) 2023 miR-1-3p Underexpressed Serum Diagnosis, Prognosis A 3-microRNA signature consisting of miR-1-3p, miR-26a-1-3p, and miR-487 b-3p was found to be differentially expressed in the serum of glioma patients compared to healthy controls. This 3-microRNA signature was specifically downregulated in the serum of glioblastoma patients with IDH wild-type tumors compared to those with IDH-mutant tumors.…”

miRNAs and related genetic biomarkers according to the WHO glioma classification: From diagnosis to future therapeutic targets

“…The signature was more downregulated in IDH -wildtype samples compared to IDH -mutant or in controls with normal IDH . Given that the three miRNAs are tumor suppressors, the authors reported that their levels were informative for OS and PFS [ 59 ].…”

The new world of RNA diagnostics and therapeutics

“…Recently, we identified a serum miRNA signature (miR-1, miR-26a-1 and miR-487b) deregulated in glioma patients according to the IDH mutation profile and correlated with the prognosis. We also showed that the three-miRNA signature displays oncosuppressive functions in glioma cells with the most marked effect on proteins crucial for migration and invasion [ 24 ] (Fig. 10 A).…”