TGF-β-activated circRYK drives glioblastoma progression by increasing VLDLR mRNA expression and stability in a ceRNA- and RBP-dependent manner

J Exp Clin Cancer Res. 2024 Mar 8;43(1):73. doi: 10.1186/s13046-024-03000-3.

Abstract

Background: The TGF-β signalling pathway is intricately associated with the progression of glioblastoma (GBM). The objective of this study was to examine the role of circRNAs in the TGF-β signalling pathway.

Methods: In our research, we used transcriptome analysis to search for circRNAs that were activated by TGF-β. After confirming the expression pattern of the selected circRYK, we carried out in vitro and in vivo cell function assays. The underlying mechanisms were analysed via RNA pull-down, luciferase reporter, and RNA immunoprecipitation assays.

Results: CircRYK expression was markedly elevated in GBM, and this phenotype was strongly associated with a poor prognosis. Functionally, circRYK promotes epithelial-mesenchymal transition and GSC maintenance in GBM. Mechanistically, circRYK sponges miR-330-5p and promotes the expression of the oncogene VLDLR. In addition, circRYK could enhance the stability of VLDLR mRNA via the RNA-binding protein HuR.

Conclusion: Our findings show that TGF-β promotes epithelial-mesenchymal transition and GSC maintenance in GBM through the circRYK-VLDLR axis, which may provide a new therapeutic target for the treatment of GBM.

Keywords: Glioblastoma; TGF-β; VLDLR; circRNA.

MeSH terms

  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma* / genetics
  • Glioblastoma* / metabolism
  • Humans
  • MicroRNAs* / metabolism
  • RNA, Circular
  • RNA, Competitive Endogenous
  • RNA, Messenger / genetics
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism

Substances

  • MicroRNAs
  • Transforming Growth Factor beta
  • RNA, Competitive Endogenous
  • RNA, Circular
  • RNA, Messenger
  • MIRN330 microRNA, human