• Exo-circRNAs: a novel potential target for cancer diagnosis and treatment
  • Roqaye Karimi,1,* Amir Atashi,2 zahra sadat mousavi,3 Monireh Ajami,4 Mansoureh Ajami,5
    1. Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
    2. Stem cell and Tissue Engineering Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
    3. Student Research Committee, Shahroud University of Medical Sciences, Shahroud, Iran
    4. Department of Medical Laboratory Sciences, School of Paramedical Sciences, Islamic Azad University Tehran Medical Sciences, Tehran, Iran
    5. Department of hematology, School of Allied Medical Sciences, Shahroud University of Medical Sciences, Shahroud, Iran


  • Introduction: Exosomes are extracellular vesicles secreted by most cells in interstitial spaces and biological fluids and usually have a diameter of 30-100 nanometers. They are important mediators of interactions between various cells and can change the behavior of the target cells. Exosomes contain a variety of molecules, including proteins, lipids, DNA fragments, miRNAs, LncRNAs, and circRNAs. It’s interesting that tumor cells secrete exosomes about 10-fold higher than other cells, and exosomal circRNAs (exo-circRNAs) are reported to have a significant role in the formation and progression of cancer through cell division, metastasis, and drug resistance.
  • Methods: The present study aimed at reviewing related scientific articles to examine and analyze the mechanism of drug resistance and chemoresistance in malignant tumors such as colorectal cancer (CRC) and the role of exo-circRNA in the development of chemoresistance in cancer cells. in this study, numbers and sizes of exosomes were examined by Nanoparticle tracking analysis (NTA) and exosomal RNA was detected by RT‐qPCR. Using tumor-implanted mice, the impacts of exo-circRNA derived from chemoresistant tumors on nonchemoresistant tumors in vivo were investigated. TargetScan, starbase and RNAhybrid were used for bioinformatics analyses. In the oxaliplatin‐resistant cell line, siRNA of PKM2 or ciRS‐122 was transfected to downregulate the expression level of PKM2 or ciRS-122 in vitro, and mouse xenograft models were used to show that exosome‐delivered si‐ciRS‐122 could increase the susceptibility of tumors to oxaliplatin in vivo.
  • Results: The exosomes of chemoresistant CRC cells contained ciRS-122 circRNA which was found to be a sponge for miR‐122. On the other hand, PKM2 led to increased glycolysis and energy production in these cells. Furthermore, upregulation of PKM2 gave transporters more energy to expel drugs from CRC cells. The researchers also showed that the exosomes of chemoresistant cells delivered ciRS-122 to chemosensitive cells, eventually increasing glycolysis and drug resistance in these cells. The important point is that the researchers succeeded to remove ciRS-122 using exosome‐delivered si‐ciRS‐122, eventually lowering PKM2 levels and increasing miR-122 levels, and also increasing the sensitivity of CRC cells to oxaliplatin in mice. This represents a potential new approach to reversing oxaliplatin resistance in CRC.
  • Conclusion: According to the results of the present study, exosomes played an important role in the development of chemoresistance in drug-sensitive cells by transferring circRNA. This intercellular signal transduction introduces a new therapeutic target for overcoming chemoresistance in tumors and may provide a basis for future clinical therapies for drug-resistant cancer cells. On the other hand, delivery of tumor suppressor circRNAs or the circRNAs encoding therapeutic proteins to exosomes could be a new cancer treatment method interested by many researchers today. Furthermore, early detection of a number of cancers is difficult due to the lack of accurate and appropriate biomarkers. Thus, identifying accurate and sensitive biomarkers to diagnose cancer seems necessary. Considering that exo-circRNAs are more stable and protected than miRNAs and other ncRNAs and have long half-lives as well as tissue-/cell-specific patterns, they can be used as potential biomarkers for early detection of cancer and response to treatment.
  • Keywords: circRNA, exosome, chemoresistance, drug resistance, cancer