Identification of low-dose radiation-induced exosomal circ-METRN and miR-4709-3p/GRB14/PDGFRα pathway as a key regulatory mechanism in Glioblastoma progression and radioresistance: Functional validation and clinical theranostic significance

Abstract

Glioblastoma is a central nervous malignancy with a very poor prognosis. This study attempted to explore the role of exosomes induced by low-dose radiation-induced (ldrEXOs) and ldrEXOs-derived circ-METRN in glioblastoma progression and radioresistance at the molecular, cellular, animal, and clinical levels. Results in the present study revealed that low-dose radiation stimulated the secretion of ldrEXOs which delivered high levels of circ-METRN. And circ-METRN-abundant ldrEXOs increased the expression of γ-H2AX, indicating an efficient DNA damage-repair process in glioblastoma cells. The ldrEXOs-derived circ-METRN enhanced the glioblastoma progression and radioresistance via miR-4709-3p/GRB14/PDGFRα pathway. Up-regulating PDGFRα can rescue the tumor-promoting function of ldrEXOs in groups previously treated with inhibition of GRB14. Additionally, in-vivo experiments revealed that treatments with ldrEXOs promoted the growth of xenografted tumors and shortened the survival period. Furthermore, clinical researches indicated that circ-METRN may be transported into the bloodstream by exosomes in the early stages of fractionated radiotherapy. It has important clinical values to detect the serum exosomal circ-METRN in the early stage of radiotherapy, which is not only conducive to predict radioresistance and prognosis but also to assist MRI diagnosis in detecting the very early recurrence of glioblastoma. In summary, this study reveals for the first time that low-dose radiation-induced exosomal circ-METRN plays an oncogenic role in glioblastoma progression and radioresistance through miR-4709-3p/GRB14/PDGFRα pathway, providing mechanistic insights into the roles of circRNAs and a valuable marker for therapeutic targets in glioblastoma.

The Role of Circular RNAs in DNA Damage Response and Repair

“…A recent study in glioblastoma cells showed that low-dose radiation triggered the secretion of exosomes containing high levels of circ-METRN, which in turn led to increased γH2AX [84]. This suggested the presence of an efficient DDRR process in glioblastoma cells.…”

“…This suggested the presence of an efficient DDRR process in glioblastoma cells. Circ-METRN was found to be responsible for tumor progression and resistance to treatment, hence exhibiting an oncogenic function through deregulation of the DDRR [84]. Another study on exosomes investigated the biology of exosomal circ-DB (circ-deubiquitination, hsa_circ_0025129), which is reciprocally related to miR-34 and negatively associated with the DNA repair player USP7 in hepatocellular carcinoma patients [85].…”

Mutual regulation between N6-methyladenosine (m6A) modification and circular RNAs in cancer: impacts on therapeutic resistance

“…Wang et al uncovered that low-dose radiation was able to induce the secretion of exosomes rich in circ-METRN. The increased circ-METRN upregulated DNA damage molecule γ-H2AX expression, but γ-H2AX level returned to normal at 24 h, indicating enhanced DNA damage repair process in radioresistant glioblastoma cells [ 167 ]. Moreover, in cisplatin-resistant GC, the PI3K/AKT pathway, which positively regulates BRCA1 expression, can be activated by circAKT3 [ 141 , 168 ].…”

Tumor-derived small extracellular vesicles: potential roles and mechanism in glioma

“…Moreover, exosome-derived circ-HIPK3 can promote TMZ-resistant GBM cell growth and TMZ resistance by modulating the miR-421/ZIC5 axis and participating in intercellular communication between GBM cells [ 102 ]. Low-dose radiation stimulates GBM cells to secrete circ-METRN-rich SEVs, and circ-METRN enhances glioblastoma progression and radioresistance by regulating the miR-4709-3p/GRB14/PDGFRα pathway [ 103 ]. Circ-0072083 in TMZ-resistant GBM tissues and cells Expression was significantly increased in both TMZ-resistant GBM tissues and cells.…”