Mesenchymal Stem Cell-Secreted Exosome Promotes Chemoresistance in Breast Cancer via Enhancing miR-21-5p-Mediated S100A6 Expression

作者：Tao Luo, Qiaoyuan Liu, Aihua Tan, Lixia Duan, Yuxian Jia, Nong Li, Jing Tang, Wenxian Zhou, Weimin Xie, Yongkui Lu, Qiang Yu, Yan Liu · 发表于：Molecular Therapy — Oncolytics · 年份：2020 · DOI：10.1016/j.omto.2020.10.008 · 被引用次数：72 · 研究领域：Extracellular vesicles in disease、MicroRNA in disease regulation、Circular RNAs in diseases

Emerging evidence has shown the role of mesenchymal stem cell-derived exosome (MSC-exo) in inducing resistance of cancer cells to chemotherapy. However, it remains unclear whether the change of MSC-exo in response to chemotherapy also contributes to chemoresistance. In this study, we investigated the effect of a standard-of-care chemotherapeutic agent, doxorubicin (Dox), on MSC-exo and its contribution to the development of Dox resistance in breast cancer cells (BCs). We found that the exosome secreted by Dox-treated MSCs (Dt-MSC-exo) induced a higher degree of Dox resistance in BCs when compared with non-treated MSC-exo. By analysis of the MSC-exo-induced transcriptome change in BCs, we identified S100A6 , a chemoresistant gene, as a top-ranked gene induced by MSC-exo in BCs, which was further enhanced by Dt-MSC-exo. Furthermore, we found that Dox induced the expression of miR-21-5p in MSCs and MSC-exo, which was required for the expression of S100A6 in BCs. Importantly, silencing of miR-21-5p expression in MSCs and MSC-exo abolished the resistance of BCs to Dox, indicating an exosomal miR-21-5p-regulated S100A6 in chemoresistance. Our study thus uncovered a novel mechanistic insight into the role of MSC-secreted exosome in the development of chemoresistance in the tumor microenvironment.