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

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

  • Cell Death Dis. 2022 Jul 11;13(7):596. doi: 10.1038/s41419-022-05056-5.
Xiuchao Geng  # 1 2,  Yuhao Zhang  # 3 4,  Xiaomeng Lin  # 5,  Zhaomu Zeng 6,  Jun Hu 7 8,  Liangchao Hao 9,  Jianglong Xu 4 6,  Xinjuan Wang 2,  Hong Wang 10 11,  Qiang Li 12
Affiliations

Affiliations

  • 1 Taizhou Central Hosiptal (Taizhou University Hospital), Taizhou University, Taizhou, 318000, Zhejiang, China.
  • 2 School of Medicine, Taizhou University, Taizhou, 318000, Zhejiang, China.
  • 3 Department of Neurosurgery, Zhejiang Provincial People's Hospital, Affiliated to Hangzhou Medical College, Hangzhou, 310000, Zhejiang, China.
  • 4 Key Laboratory of Precise Diagnosis and Treatment of Glioma in Hebei Provience, Baoding, 071000, Hebei, China.
  • 5 Departments of Breast Surgery, Affiliated Hospital of Hebei University, Baoding, 071000, Hebei, China.
  • 6 Department of Neurosurgery, Affiliated Hospital of Hebei University, Baoding, 071000, Hebei, China.
  • 7 Faculty of Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, 050091, Hebei, China.
  • 8 Department of Neurosurgery, Affiliated Hospital of Chengde medical University, Chengde, 067000, Hebei, China.
  • 9 Department of Plastic Surgery, Shaoxing People's Hospital, Shaoxing, 312000, Zhejiang, China.
  • 10 Department of Neurosurgery, Affiliated Hospital of Hebei University, Baoding, 071000, Hebei, China. [email protected].
  • 11 Faculty of Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, 050091, Hebei, China. [email protected].
  • 12 School of Medicine, Taizhou University, Taizhou, 318000, Zhejiang, China. [email protected].
  • # Contributed equally.
PMID: 35817771 DOI: 10.1038/s41419-022-05056-5
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.

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