<p>Adipose Mesenchymal Stem Cell-Derived Exosomal microRNA-1236 Reduces Resistance of Breast Cancer Cells to Cisplatin by Suppressing SLC9A1 and the Wnt/β-Catenin Signaling</p>

Abstract

Background: Emerging evidence has noted the versatile functions of mesenchymal stem cell-derived exosomes (MSC-Exos) in cancer control. This work aims to probe to function of adipose MSC-Exos (adMSC-Exos) in drug-resistance of breast cancer (BC) cells to cisplatin (DDP) and the molecules involved. Methods: Parental and DDP-resistant BC cell lines MCF-7 and MDA-MB-231 were used. All cells were pre-treated with adMSC-Exos. Then, the viability and apoptosis of cells after DDP treatment were determined. Differentially expressed miRNAs after adMSC-exo treatment were screened out. Rescue experiments were conducted by pre-transfecting miR-1236 inhibitor into adMSCs, and the role of miR-1236 in DDP sensitivity was determined. Targeting mRNAs of miR-1236 were predicted by bioinformatics analysis. Altered SLC9A1 expression was administrated to evaluate its function in DDP resistance. Results: The adMSC-Exos notably increased the sensitivity of either parental or DDPresistant BC cells to DDP. SLC9A1 was notably highly expressed in DDP-resistant cells but inhibited following adMSC-exo administration. Importantly, miR-1236, which could directly bind to SLC9A1 and suppress its expression, was confirmed as an enriched miRNA in adMSC-Exos. Either inhibition of miR-1236 or upregulation of SLC9A1 blocked the pro-sensitize roles of adMSC-Exos. In addition, the Wnt/β-catenin pathway activity was suppressed by adMSC-Exos but recovered by SLC9A1. Conclusion: This study evidenced that adMSC-Exos carry miR-1236 to increase sensitivity of BC cells to DDP with the involvement of SLC9A1 downregulation and Wnt/β-catenin inactivation. This finding may offer novel insights into treatment for drug-resistant BC.

Drug Resistance in Metastatic Breast Cancer: Tumor Targeted Nanomedicine to the Rescue

“…EMT is a process that converts polarized in treatment sensitive cells through the transfer of miR-155 [ 304 ]. Adipose mesenchymal stem cell-derived miR-1236 in exosomes sensitized the breast cancer cells to cisplatin treatment by inhibiting the Wnt/β-catenin signaling [ 305 ]. Exosomes obtained from human umbilical cord mesenchymal stem cells exhibit inhibitory effects on the breast cancer cells in vitro and in vivo.…”

MSCs as Tumor-Specific Vectors for the Delivery of Anticancer Agents—A Potential Therapeutic Strategy in Cancer Diseases: Perspectives for Quinazoline Derivatives

“…The study suggests that MSCs can increase β-catenin expression and stimulate Wnt activity by MSC-secreted soluble factors and the previously mentioned molecular mechanisms [ 82 ]. On the other hand, there is research that underscores the importance of MSCs in inhibiting the proliferation, invasion, and migration of cancer cells through the Wnt signaling pathway [ 83 , 84 ]. It has been reported that MSC-derived exosomes containing miR-133b suppress glioma development by inhibiting EZH2 and the Wnt/β-catenin signaling pathway [ 83 ].…”

“…Recent studies have also shown that exosomes derived from MSCs may play a significant role in cancer control. Jia et al found that adipose derived MSC-exosomes containing miR-1236 increase the sensitivity of breast cancer to cisplatin with the involvement of SLC9A1 downregulation and Wnt/β-catenin inactivation [ 84 ]. Torsvik et al indicate that tumor growth can also be inhibited by MSC secreted inflammation cytokines, by Dkk-1 and the subsequent inhibition of the Wnt/β-catenin pathway [ 78 ].…”

“…MSC produce vesicles that contain small-molecule anticancer agents. The presence of extracellular vesicles (EVs) between MSCs and cancer cells suggests that the small-molecule anticancer agent can be delivered to cancer cells in a vesicular system [ 84 ].…”

Breast Cancer Microenvironment Cross Talk through Extracellular Vesicle RNAs

“…Exosomes derived from adipose tissue mesenchymal stem cells contain miR-1236, which down-regulates Solute Carrier Family 9 Member A1 (SLC9A1) and the Wnt/b-catenin pathway. 94 This sensitizes the breast cancer cells to cisplatin treatment. Another study 95 showed increased resistance to doxorubicin in breast cancer cells in the presence of adipocytes.…”