Exosomal circWDR62 promotes temozolomide resistance and malignant progression through regulation of the miR-370-3p/MGMT axis in glioma

Abstract

Exosome-mediated delivery of circular RNAs (circRNAs) is implicated in cancer progression. However, the role of exosomal circRNAs in the chemotherapy resistance of tumours remains poorly understood. Here we identified a novel circRNA, circWDR62. It was found that circWDR62 expression was upregulated in TMZ-resistant glioma cells and TMZ-resistant glioma cell-derived exosomes compared with their controls by using high-throughput microarray analysis and quantitative real-time polymerase chain reaction, and high circWDR62 expression was associated with poor prognosis of glioma. Functionally, downregulation of circWDR62 expression could significantly inhibit the TMZ resistance and malignant progression of glioma. Further mechanistic studies showed that circWDR62 plays a role by sponging miR-370-3p as a competing endogenous RNA. Rescue experiments confirmed that MGMT is the downstream target of the circWDR62/miR-370-3p axis in glioma. In addition, circWDR62 could be transported between TMZ-resistant and TMZ-sensitive glioma cells via exosomes. Exosomal circWDR62 from TMZ-resistant cells conferred TMZ resistance in recipient sensitive cells while also enhancing the proliferation, migration and invasion of these cells. A series of clinical and in vivo trials corroborated that exosomal circWDR62 could promote TMZ chemoresistance and malignant progression of glioma. Our results demonstrate for the first time that exosome-mediated delivery of circWDR62 can promote TMZ resistance and malignant progression via targeting of the miR-370-3p/MGMT axis in vitro and in vivo in glioma, providing a new therapeutic strategy. Moreover, exosomal circWDR62 in human serum may serve as a promising therapeutic target and prognostic marker for glioma therapy.

Antisense lncRNA NNT-AS1 promoted esophageal squamous cell carcinoma progression by regulating its sense gene NNT expression

“…The extracted RNAs were reversely transcribed to cDNAs using PrimeScriptTM II Reverse Transcriptase (Takara, Tokyo, Japan). Gene expression was calculated as previously reported [ 34 ]. Primer sequences were illustrated in Table S1 .…”

Exosomal circRNAs as promising liquid biopsy biomarkers for glioma

“…Exosomal circRNAs also play an important role in the development of glioma, including proliferation, immunosuppression, angiogenesis, invasion, migration, and therapeutic resistance. Recent studies have shown that exosomeassociated circRNAs such as circ_104948, circ_0001445, circHIPK3, circWDR62, circMMP1, circ_0012381 play roles in the glioma proliferation process through miRNAs (30,(96)(97)(98)(99)(100). CircNEIL3 promotes glioma progression and exosome-mediated macrophage immunosuppressive polarization via stabilizing IGF2BP3 (101).…”

“…Macrophage-derived exosomes circBTG2 overexpression inhibited proliferation and invasion of glioma cells, circMMP1, and circSMARCA5 (circ_0001445) also play roles in the process of invasion and migration (30,98,103,104). Low-dose radiation-induced exosomal circ-METRN plays an oncogenic role in glioblastoma progression and radioresistance through miR-4709-3p/GRB14 pathway; circ_0072083, circWDR62, circ_0042003, circNFIX, circHIPK3, circGLIS3 can resist TMZ in the treatment of glioma (96,97,(105)(106)(107)(108)(109). Figure 2 shows the roles by which exosomal circRNAs may be involved in the development of glioma.…”

Unraveling the significance of exosomal circRNAs in cancer therapeutic resistance

“…Analogously, Han et al demonstrated that aberrantly expressed exosomal circHIPK3 could accelerate the cancer progression and TMZ resistance by adjusting the miR-421/ZIC5 signaling axis ( Han et al, 2021 ). Geng et al demonstrated the exosome-mediated delivery of circWDR62 in TMZ-resistant glioma cells U251-R. High expression of exosomal circWDR62 can enhance TMZ resistance and malignant progression via regulating the miR-370-3p/MGMT axis ( Geng et al, 2022 ).…”