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

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 DDP-resistant 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/?-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/?-catenin inactivation. This finding may offer novel insights into treatment for drug-resistant BC.

SUBMITTER: Jia Z

PROVIDER: S-EPMC7519869 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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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.

Jia Zhongming Z Zhu Huamin H Sun Hongguang H Hua Yitong Y Zhang Guoqiang G Jiang Jingru J Wang Xiaohong X

Cancer management and research 20200922

<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 33061571

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Project description:BackgroundCompared with the precise targeting of drug-resistant mutant cancer cells, strategies for eliminating non-genetic adaptation-mediated resistance are limited. The pros and cons of the existence of inflammasomes in cancer have been reported. Nevertheless, the dynamic response of inflammasomes to therapies should be addressed.MethodsTumor-derived exosomes were purified by differential ultracentrifugation and validated by nanoparticle tracking analysis and transmission electron microscopy. A proximity ligation assay and interleukin-1β (IL-1β) level were used for detecting activation of NLRP3 inflammasomes. RNA sequencing was used to analyze the exosomal RNAs. MIR21 knocked out human monocytic THP cells and mir21 knocked out murine oral cancer MTCQ1 cells were generated for confirming the exosomal delivery of microRNA (miR)-21. Syngeneic murine models for head and neck cancer (C57BLJ/6J), breast cancer (BALB/C) and lung cancer (C57BL/6J) were applied for examining the impact of Snail-miR21 axis on inflammasome activation in vivo. Single-cell RNA sequencing was used for analyzing the tumor-infiltrated immune cells. Head and neck patient samples were used for validating the findings in clinical samples.ResultsWe demonstrated that in cancer cells undergoing Snail-induced epithelial-mesenchymal transition (EMT), tumor cells suppress NLRP3 inflammasome activities of tumor-associated macrophages (TAMs) in response to chemotherapy through the delivery of exosomal miR-21. Mechanistically, miR-21 represses PTEN and BRCC3 to facilitate NLRP3 phosphorylation and lysine-63 ubiquitination, inhibiting NLRP3 inflammasome assembly. Furthermore, the Snail-miR-21 axis shapes the post-chemotherapy tumor microenvironment (TME) by repopulating TAMs and by activating CD8+ T cells. In patients with head and neck cancer, the Snail-high cases lacked post-chemotherapy IL-1β surge and were correlated with a worse response.ConclusionsThis finding reveals the mechanism of EMT-mediated resistance beyond cancer stemness through modulation of post-treatment inflammasome activity. It also highlights the dynamic remodeling of the TME throughout metastatic evolution.

Dataset Information

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

Publications

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.

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