Abstract

   Breast-to-brain metastatic (BTB met) cancer constitutes a great
   challenge for modern medicine and science, and thus, a quest for the
   discovery of novel therapeutic targets is underway. As the research on
   protein-coding genes has brought only incremental progress in
   discovering such targets, much attention is currently devoted to
   understanding the role of non-coding RNAs, including a relatively
   recently discovered group of circular RNAs. These non-coding RNAs,
   which arise from linear RNA transcripts, possess a covalently closed
   structure that renders them resistant to RNA turnover and a specific
   circularization site sequence that allows their precise suppression
   while keeping the linear parental transcript intact. These features
   thus make them promising candidates for biomarkers and therapeutic
   targets. This project aimed to map the circular RNA landscape in a
   comprehensive model of BTB met cancer cells, primary breast carcinoma,
   primary brain tumor cells, and relevant non-malignant breast and brain
   cell controls. Despite different tissue-of-origin, the analysis of
   global circRNAomes showed striking similarities between BTB mets and
   glioblastoma stem-like cells (GSCs) and allowed the selection of
   reliable candidates for mechanistic studies. Interestingly, the
   circRNAome of BTB mets clustered particularly closely with mesenchymal
   GSC, the most aggressive and therapy-resistant subtype of GSCs.
   Efficient knockdown of candidate circular RNAs in BTB met cells by
   antisense oligonucleotides resulted in molecular and phenotypic
   alterations such as diminished viability and clonality, arrested cell
   cycle concurrent with increased expression of cyclin-dependent kinase
   inhibitors, and changed expression of epithelial-mesenchymal transition
   markers. These results thus demonstrated the role of circular RNAs in
   shaping the oncogenic traits of BTB met cells. Further research focuses
   on circular RNA-dependent chemotherapy resistance,
   stemness/differentiation balance, and relevant models of metastatic
   progression (primary site/pleural effusion/brain). Therefore, circular
   RNAs can serve as valuable biomarkers and promising novel mechanistic
   candidates whose modulation may become a paradigm-shifting therapeutic
   approach.
     __________________________________________________________________

   Articles from Neuro-Oncology Advances are provided here courtesy of
   Oxford University Press
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