Circulating miRNAs as a novel biomarkers and intercellular regulators in glioma

Abstract

Glioma is the most common intracranial malignant cancer despite the rarity. Glioblastoma (GBM, grade IV) has very dismal outcomes where fewer than 20% of patients survive beyond 5 years. Low Grade Glioma (LGG, grade II), on the other hand, frequently occurs in a younger population with a variable outcome that depends on their individual genetic alterations. A tissue-based biopsy requires an invasive operation for every glioma patient and it is the gold standard diagnosis. In monitoring the patients for recurrence, MRI has the evitable limitation that it could not differentiate pseudo-progression after irradiation treatment for glioma patients. Therefore, a non-invasive biomarker, in addition to tissue biopsy and MRI, is urgently needed to provide more precise cancer care and management with glioma patients. In fact, cancer cells including glioma cells, release microRNA (miRNA) into the microenvironment and peripheral circulation, which allows physicians and scientists the ability to detect the disease status by a blood test. In addition, microRNA (miRNA) displays accuracy in diagnosing and monitoring other cancer patients by analysis of miRNA abundance. To investigate the diagnostic capacity of circulating miRNA in glioma, a meta-analysis of previous relevant studies was performed. Circulating miRNA provided an over 90% accuracy of diagnosing glioma patients from healthy controls. A bioinformatic analysis revealed seven IDH1 mutation-associated miRNAs and these miRNA signatures were down-regulated in IDH1 mutant glioblastoma due to the hypermethylation in their promoter areas. Our proof-of-concept cohort recruited 91 glioma patients and 17 healthy controls and new circulating miRNAs were identified with remarkable diagnostic capacity. However, no circulating miRNA showed an association with IDH1 mutation in our cohort. As most circulating miRNAs were packaged and delivered by extracellular vesicles (EVs), serial cell experiments were conducted to examine the function of these miRNA-enriched EVs. Glioma Stem Cells-derived EVs significantly promoted glioma cell proliferation, cell migration and radiation resistance. This effect was largely caused by the degradation of PTEN and activation of AKT in the recipient cells through miRNAs. Collectively, these works established circulating miRNA as a clinical biomarker where it provides a complementary tool for glioma management. These results also formed the basis of future research into the role of EVs in glioma and highlighted the potential therapeutic target of EVs to glioma.