Delivery of LNA-antimiR-142-3p by Mesenchymal Stem Cells-Derived Exosomes to Breast Cancer Stem Cells Reduces Tumorigenicity.

Exosomes, nano-sized cell-derived vesicles, have been employed as non-synthetic carriers of various pharmaceutics in numerous studies. As higher expression levels of miR-142-3p and miR-150 in breast cancer stem cells (BCSCs) are associated with their clonogenic and tumorigenic capabilities, the present study aims to exploit the mesenchymal stem cells-derived exosomes (MSCs-Exo) to deliver LNA-antimiR-142-3p into MCF7-derived cancer stem-like cells to suppress expression levels of miR-142-3p and miR-150 in order to reduce clonogenicity and tumorigenicity. Our results indicated that the MSCs-Exo can efficiently deliver the LNA-antimiR-142-3p to breast cancer stem-like cells to reduce the miR-142-3p and miR-150 expression levels. Furthermore, the inhibition of the oncomiRs with the delivery of LNA-antimiR-142-3p resulted in a significant reduction of clone-formation and tumor-initiating abilities of the MCF7-derived cancer stem-like cells. In conclusion, we showed that MSCs-derived exosomes could be used as a feasible nanovehicles to deliver RNA-based therapeutics into BCSCs to improve the cancer treatment. HIGHLIGHTS: Exosomes secreted by bone marrow-derived mesenchymal stem cells efficiently transfer the LNA-antimiR-142-3p to breast cancer stem cells. Exosomes-mediated delivery of LNA-antimiR-142-3p to the breast cancer stem cells leads to downregulation of miR-142-3p and miR-150 and the overexpression of target genes. Delivery of LNA-antimiR-142-3p by the exosomes reduces the colony formation capability of breast cancer stem cells in vitro. Inhibition of miR-142-3p and miR-150 by the LNA-antimiR-142-3p loaded exosomes reduces the tumorigenicity of breast cancer stem cells in vivo.

Exosome-mediated delivery of functionally active miRNA-142-3p inhibitor reduces tumorigenicity of breast cancer in vitro and in vivo.

BACKGROUND: Exosomes, widely recognized natural nanovesicles, represent one of the recently discovered modes of intercellular communication due to their ability to transmit crucial cellular information that can be engineered to have robust delivery and targeting capacity. MiR-142-3p, one of the upregulated microRNAs (miRNAs) in many types of breast cancer, activates the canonical Wnt signaling pathway and transactivates the miR-150 expression, and results in the hyperproliferation of cancer cells in vitro and mammary glands in vivo. MATERIALS AND METHODS: In this study, we exploited the exosomes isolated from bone marrow-derived mesenchymal stem cells (MSCs-Exo) to deliver LNA (locked nucleic acid)-modified anti-miR-142-3p oligonucleotides to suppress the expression level of miR-142-3p and miR-150 in 4T1 and TUBO breast cancer cell lines. RESULTS: The in vitro results showed that the MSCs-Exo can efficiently deliver anti-miR-142-3p to reduce the miR-142-3p and miR-150 levels and increase the transcription of the regulatory target genes, APC and P2X7R. We also evaluated in vivo distribution of the MSCs-Exo in tumor-bearing mice. The in vivo result indicated that MSCs-Exo can penetrate the tumor site and are suitable nanovehicles to deliver the inhibitory oligonucleotides into the tumor tissues to downregulate the expression levels of miR-142-3p and miR-150. CONCLUSION: We showed that MSCs-derived exosomes could be used as a feasible nanovehicle to deliver drug molecules like LNA-anti-miR-142-3p in both in vitro and in vivo studies.