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  • Mesenchymal Stem Cell-Derived Exosomal Non-Coding RNAs as Suppressors of Hepatocellular Carcinoma Progression

  • Parisa Gozali,1 Mohammad Reza Sadeghi,2 Parastou Mirzaei,3 Maryam Anari,4 Abolfazl Barzegari,5,*
    1. Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
    2. Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
    3. Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
    4. Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
    5. Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.


  • Introduction: Hepatocellular carcinoma (HCC) is a complex disease with diverse etiological causes and is the second leading cause of cancer-related mortality worldwide due to its high rate of recurrence (Xu et al., 2021). Mesenchymal stromal cells (MSCs) are commonly employed as a cell-based therapeutic approach because of their distinctive characteristics for regeneration and immunosuppression (Ma et al., 2021). Exosomes carry diverse functional non-coding RNA (ncRNA) into recipient cells, where these molecules influence a wide range of biological pathways and cellular activities (Pant et al., 2021). Recent studies have demonstrated that MSC-derived exosomal ncRNAs can directly regulate HCC progression through modulation of key molecular pathways involved in tumor growth, invasion and epithelial-mesenchymal transition (EMT).
  • Methods: We searched the PubMed and Google Scholar databases using relevant keywords, including mesenchymal stem cell, exosomes and hepatocellular carcinoma, to identify the latest original articles published over the last 5 years that involved MSCs-Derived Exosomes in hepatocellular carcinoma.
  • Results: Several studies have demonstrated that MSC-derived exosomal ncRNAs can have direct antitumor effects by regulating key pathways involved in EMT, proliferation, invasion, and apoptosis. Among these regulatory mechanisms, inhibition of EMT represents a major mechanism through which MSC-derived exosomal miRNAs suppress HCC aggressiveness. Exosomal miR-374c-5p derived from bone marrow MSCs was shown to suppress EMT of HCC cells via the LIMK1-Wnt/β-catenin axis. The transfer of exosomal miR-374c-5p suppressed invasion, migration and proliferation of HCC cells (Ding et al., 2023). Similarly, human umbilical cord MSC-derived exosomal miR-451a also repressed EMT of HCC cells by inhibiting ADAM10. HucMSC-derived exosomes increased miR-451a expression and decreased ADAM10 expression in HCC cells. Exosomal miR-451a suppressed cell cycle transition, proliferation, migration, invasion and paclitaxel resistance, while promoting apoptosis of HCC cells (Xu et al., 2021). Beyond EMT regulation, MSC-derived exosomal miRNAs can suppress HCC progression by targeting oncogenic regulators involved in malignant cell behavior. Exosomal miR-15a derived from MSCs inhibited HCC progression through downregulation of SALL4. The exosomes from MSCs restrained migration, proliferation and invasion potentials and accelerated apoptosis in HCC cells (Ma et al., 2021). Although most studies have focused on exosomal miRNAs, emerging evidence indicates that exosomal lncRNAs also contribute to the direct suppression of HCC progression. Human umbilical cord MSC-derived exosomal lncRNA FAM99B inhibited malignant cellular phenotypes and tumorigenesis in HCC. Exosomal lncRNA FAM99B enhanced cell cycle arrest and cell apoptosis while suppressing cell migration, viability and invasion (Xu et al., 2024).
  • Conclusion: MSC-derived exosomal ncRNAs directly regulate hepatocellular carcinoma progression by targeting key molecular pathways involved in EMT, proliferation, invasion and apoptosis. These findings highlight the potential of exosomal miRNAs and lncRNAs as promising therapeutic regulators for HCC treatment.
  • Keywords: hepatocellular carcinoma, mesenchymal stem cell, exosomes, ncRNA.

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