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European Journal of Medical Research
Published in: European Journal of Medical Research 1/2023

Open Access 01-12-2023 | Breast Cancer | Research

Mesenchymal stem cell-derived exosomes enriched with miR-218 reduce the epithelial–mesenchymal transition and angiogenesis in triple-negative breast cancer cells

Authors: Samaneh Shojaei, Maryam Moradi-Chaleshtori, Mahdi Paryan, Ameneh Koochaki, Kazem Sharifi, Samira Mohammadi-Yeganeh

Published in: European Journal of Medical Research | Issue 1/2023

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Abstract

Background

The epithelial–mesenchymal transition (EMT) and angiogenesis are morphogenetic processes implicated in tumor invasion and metastasis. It is found that the aberrant expression of microRNAs (miRNAs) contributes to these processes. Exosomes are considered potential natural vehicles for miRNA delivery in cancer therapy. miR-218 is one of the tumor suppressor miRNAs and its downregulation is associated with EMT and angiogenesis. We aimed to use adipose mesenchymal stem cells-derived exosomes (ADMSC-exosomes) for miR-218 delivery to breast cancer cells and evaluate miR-218 tumor-suppressing properties in vitro.

Methods

Exosomes were isolated from conditioned media of ADMSCs. miR-218 was loaded to exosomes using electroporation. mRNA expression of target genes (Runx2 and Rictor) in MDA-MB-231 breast cancer cells was evaluated by qPCR. To explore the effects of miR-218 containing exosomes on breast cancer cells, viability, apoptosis, and Boyden chamber assays were performed. The angiogenic capacity of MDA-MB-231 cells after treatment with miR-218 containing exosomes was assessed by in vitro tube formation assay.

Results

miR-218 mimic was efficiently loaded to ADMSC-exosomes and delivered to MDA-MB-231 cells. Exposure to miR-218 containing exosomes significantly decreased miR-218 target genes (Runx2 and Rictor) in MDA-MB-231 cells. They increased the expression of epithelial marker (CDH1) and reduced mesenchymal marker (CDH2). miR-218 restoration using miR-218 containing exosomes reduced viability, motility, invasion, and angiogenic capacity of breast cancer cells.

Conclusions

These findings suggest that ADMSC-exosomes can efficiently restore miR-218 levels in breast cancer cells and miR-218 can prevent breast cancer progression with simultaneous targeting of angiogenesis and EMT.
Literature
1.
2.
3.
Garzon R, Marcucci G, Croce CM. Targeting microRNAs in cancer: rationale, strategies and challenges. Nat Rev Drug Discovery. 2010;9(10):775–89.CrossRefPubMed
4.
Fu Y, Chen J, Huang Z. Recent progress in microRNA-based delivery systems for the treatment of human disease. ExRNA. 2019;1(1):24.CrossRef
5.
Ruivo CF, Adem B, Silva M, Melo SA. The biology of cancer exosomes: insights and new perspectives. Can Res. 2017;77(23):6480–8.CrossRef
6.
Baumann V, Winkler J. miRNA-based therapies: strategies and delivery platforms for oligonucleotide and non-oligonucleotide agents. Future Med Chem. 2014;6(17):1967–84.CrossRefPubMed
7.
8.
Shi ZM, Wang L, Shen H, Jiang CF, Ge X, Li DM, et al. Downregulation of miR-218 contributes to epithelial-mesenchymal transition and tumor metastasis in lung cancer by targeting Slug/ZEB2 signaling. Oncogene. 2017;36(18):2577–88.CrossRefPubMedPubMedCentral
9.
Tie J, Pan Y, Zhao L, Wu K, Liu J, Sun S, et al. MiR-218 inhibits invasion and metastasis of gastric cancer by targeting the Robo1 receptor. PLoS Genet. 2010;6(3):e1000879.CrossRefPubMedPubMedCentral
10.
Li N, Wang L, Tan G, Guo Z, Liu L, Yang M, et al. MicroRNA-218 inhibits proliferation and invasion in ovarian cancer by targeting Runx2. Oncotarget. 2017;8(53):91530–41.CrossRefPubMedPubMedCentral
11.
Lun W, Wu X, Deng Q, Zhi F. MiR-218 regulates epithelial-mesenchymal transition and angiogenesis in colorectal cancer via targeting CTGF. Cancer Cell Int. 2018;18:83.CrossRefPubMedPubMedCentral
12.
Han M, Chen L, Wang Y. miR-218 overexpression suppresses tumorigenesis of papillary thyroid cancer via inactivation of PTEN/PI3K/AKT pathway by targeting Runx2. Onco Targets Ther. 2018;11:6305–16.CrossRefPubMedCentral
13.
Liu Y, Cai Q, Bao PP, Su Y, Cai H, Wu J, et al. Tumor tissue microRNA expression in association with triple-negative breast cancer outcomes. Breast Cancer Res Treat. 2015;152(1):183–91.CrossRefPubMedPubMedCentral
14.
Setijono SR, Park M, Kim G, Kim Y, Cho KW, Song SJ. miR-218 and miR-129 regulate breast cancer progression by targeting Lamins. Biochem Biophys Res Commun. 2018;496(3):826–33.CrossRef
15.
He X, Xiao X, Dong L, Wan N, Zhou Z, Deng H, et al. MiR-218 regulates cisplatin chemosensitivity in breast cancer by targeting BRCA1. Tumour biol. 2015;36(3):2065–75.CrossRefPubMed
16.
Hu Y, Xu K, Yagüe E. miR-218 targets survivin and regulates resistance to chemotherapeutics in breast cancer. Breast Cancer Res Treat. 2015;151(2):269–80.CrossRefPubMed
17.
Liu X, Cao M, Palomares M, Wu X, Li A, Yan W, et al. Metastatic breast cancer cells overexpress and secrete miR-218 to regulate type I collagen deposition by osteoblasts. Breast Cancer Res. 2018;20(1):127.CrossRefPubMedPubMedCentral
18.
Zhang H, Zhang Y, Chen C, Zhu X, Zhang C, Xia Y, et al. A double-negative feedback loop between DEAD-box protein DDX21 and Snail regulates epithelial-mesenchymal transition and metastasis in breast cancer. Cancer Lett. 2018;437:67–78.CrossRefPubMed
19.
20.
Kia V, Paryan M, Mortazavi Y, Biglari A, Mohammadi-Yeganeh S. Evaluation of exosomal miR-9 and miR-155 targeting PTEN and DUSP14 in highly metastatic breast cancer and their effect on low metastatic cells. J Cell Biochem. 2019;120(4):5666–76.CrossRefPubMed
21.
Todorova K, Zasheva D, Kanev K, Hayrabedyan S. miR-204 shifts the epithelial to mesenchymal transition in concert with the transcription factors RUNX2, ETS1, and cMYB in prostate cancer cell line model. J Cancer Res. 2014;2014:840906.CrossRef
22.
Niu DF, Kondo T, Nakazawa T, Oishi N, Kawasaki T, Mochizuki K, et al. Transcription factor Runx2 is a regulator of epithelial-mesenchymal transition and invasion in thyroid carcinomas. Lab Invest. 2012;92(8):1181–90.CrossRefPubMed
23.
Khazaei-Poul Y, Shojaei S, Koochaki A, Ghanbarian H, Mohammadi-Yeganeh S. Evaluating the influence of human umbilical cord mesenchymal stem cells-derived exosomes loaded with miR-3182 on metastatic performance of triple negative breast cancer cells. Life Sci. 2021;286:120015.CrossRefPubMed
24.
Li X, Liu LL, Yao JL, Wang K, Ai H. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles inhibit endometrial cancer cell proliferation and migration through delivery of exogenous miR-302a. Stem Cells Int. 2019;2019:8108576.CrossRefPubMedPubMedCentral
25.
Zhang X, Dong J, He Y, Zhao M, Liu Z, Wang N, et al. miR-218 inhibited tumor angiogenesis by targeting ROBO1 in gastric cancer. Gene. 2017;615:42–9.CrossRefPubMed
26.
Guan B, Wu K, Zeng J, Xu S, Mu L, Gao Y, et al. Tumor-suppressive microRNA-218 inhibits tumor angiogenesis via targeting the mTOR component RICTOR in prostate cancer. Oncotarget. 2017;8(5):8162–72.CrossRef
27.
Tang M, Liu Y, Zhang QC, Zhang P, Wu JK, Wang JN, et al. Antitumor efficacy of the Runx2-dendritic cell vaccine in triple-negative breast cancer in vitro. Oncol Lett. 2018;16(3):2813–22.PubMedPubMedCentral
28.
Watanabe R, Miyata M, Oneyama C. Rictor promotes tumor progression of rapamycin-insensitive triple-negative breast cancer cells. Biochem Biophys Res Commun. 2020;531(4):636–42.CrossRefPubMed
29.
Onodera Y, Miki Y, Suzuki T, Takagi K, Akahira J, Sakyu T, et al. Runx2 in human breast carcinoma: its potential roles in cancer progression. Cancer Sci. 2010;101(12):2670–5.CrossRefPubMed
30.
Pratap J, Javed A, Languino LR, van Wijnen AJ, Stein JL, Stein GS, et al. The Runx2 osteogenic transcription factor regulates matrix metalloproteinase 9 in bone metastatic cancer cells and controls cell invasion. Mol Cell Biol. 2005;25(19):8581–91.CrossRefPubMedPubMedCentral
31.
Kwon TG, Zhao X, Yang Q, Li Y, Ge C, Zhao G, et al. Physical and functional interactions between Runx2 and HIF-1α induce vascular endothelial growth factor gene expression. J Cell Biochem. 2011;112(12):3582–93.CrossRefPubMedPubMedCentral
32.
Lee SH, Che X, Jeong JH, Choi JY, Lee YJ, Lee YH, et al. Runx2 protein stabilizes hypoxia-inducible factor-1α through competition with von Hippel-Lindau protein (pVHL) and stimulates angiogenesis in growth plate hypertrophic chondrocytes. J Biol Chem. 2012;287(18):14760–71.CrossRefPubMed
33.
El Shamieh S, Saleh F, Moussa S, Kattan J, Farhat F. RICTOR gene amplification is correlated with metastasis and therapeutic resistance in triple-negative breast cancer. Pharmacogenomics. 2018;19(9):757–60.CrossRefPubMed
34.
Morrison Joly M, Hicks DJ, Jones B, Sanchez V, Estrada MV, Young C, et al. Rictor/mTORC2 drives progression and therapeutic resistance of HER2-amplified breast cancers. Can Res. 2016;76(16):4752–64.CrossRef
35.
Lamanuzzi A, Saltarella I, Desantis V, Frassanito MA, Leone P, Racanelli V, et al. Inhibition of mTOR complex 2 restrains tumor angiogenesis in multiple myeloma. Oncotarget. 2018;9(29):20563–77.CrossRefPubMedPubMedCentral
36.
37.
Jiao Z, Ma Y, Wang Y, Liu T, Zhang Q, Liu X, et al. Protective effect of adipose-derived mesenchymal stem cell secretome against hepatocyte apoptosis induced by liver ischemia-reperfusion with partial hepatectomy injury. Stem Cells Int. 2021;2021:9969372.CrossRefPubMedPubMedCentral
38.
Lopatina T, Mazzeo A, Bruno S, Tetta C, Natalia K, Romagnoli R, et al. The angiogenic potential of adipose mesenchymal stem cell-derived extracellular vesicles is modulated by basic fibroblast growth factor. J Stem Cell Res Ther. 2014;2014:245–512014.
39.
Zhang B, Wu X, Zhang X, Sun Y, Yan Y, Shi H, et al. Human umbilical cord mesenchymal stem cell exosomes enhance angiogenesis through the Wnt4/β-catenin pathway. Stem Cells Transl Med. 2015;4(5):513–22.CrossRefPubMedPubMedCentral
40.
Lee JK, Park SR, Jung BK, Jeon YK, Lee YS, Kim MK, et al. Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells. PLoS ONE. 2013;8(12):e84256.CrossRefPubMedPubMedCentral
41.
Pakravan K, Babashah S, Sadeghizadeh M, Mowla SJ, Mossahebi-Mohammadi M, Ataei F, et al. MicroRNA-100 shuttled by mesenchymal stem cell-derived exosomes suppresses in vitro angiogenesis through modulating the mTOR/HIF-1α/VEGF signaling axis in breast cancer cells. Cell Oncol (Dordr). 2017;40(5):457–70.CrossRefPubMed
42.
Naseri Z, Oskuee RK, Jaafari MR, Forouzandeh MM. Exosome-mediated delivery of functionally active miRNA-142-3p inhibitor reduces tumorigenicity of breast cancer in vitro and in vivo. Int J Nanomed. 2018;13:7727–47.CrossRef
43.
Naseri Z, Oskuee RK, Forouzandeh-Moghadam M, Jaafari MR. Delivery of LNA-antimiR-142-3p by mesenchymal stem cells-derived exosomes to breast cancer stem cells reduces tumorigenicity. Stem Cell Rev Rep. 2020;16(3):541–56.CrossRefPubMed
44.
O’Brien KP, Khan S, Gilligan KE, Zafar H, Lalor P, Glynn C, et al. Employing mesenchymal stem cells to support tumor-targeted delivery of extracellular vesicle (EV)-encapsulated microRNA-379. Oncogene. 2018;37(16):2137–49.CrossRefPubMed
Metadata
Title
Mesenchymal stem cell-derived exosomes enriched with miR-218 reduce the epithelial–mesenchymal transition and angiogenesis in triple-negative breast cancer cells
Authors
Samaneh Shojaei
Maryam Moradi-Chaleshtori
Mahdi Paryan
Ameneh Koochaki
Kazem Sharifi
Samira Mohammadi-Yeganeh
Publication date
01-12-2023
Publisher
BioMed Central
Published in
European Journal of Medical Research / Issue 1/2023
Electronic ISSN: 2047-783X
DOI
https://doi.org/10.1186/s40001-023-01463-2

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