Exosome-mediated microRNA signaling from breast cancer cells is altered by the anti-angiogenesis agent docosahexaenoic acid (DHA)
Open accessAbstract
BACKGROUND: Docosahexaenoic acid (DHA) is a natural compound with anticancer and anti-angiogenesis activity that is currently under investigation as both a preventative agent and an adjuvant to breast cancer therapy. However, the precise mechanisms of DHA's anticancer activities are unclear. It is understood that the intercommunication between cancer cells and their microenvironment is essential to tumor angiogenesis. Exosomes are extracellular vesicles that are important mediators of intercellular communication and play a role in promoting angiogenesis. However, very little is known about the contribution of breast cancer exosomes to tumor angiogenesis or whether exosomes can mediate DHA's anticancer action. RESULTS: Exosomes were collected from MCF7 and MDA-MB-231 breast cancer cells after treatment with DHA. We observed an increase in exosome secretion and exosome microRNA contents from the DHA-treated cells. The expression of 83 microRNAs in the MCF7 exosomes was altered by DHA (>2-fold). The most abundant exosome microRNAs (let-7a, miR-23b, miR-27a/b, miR-21, let-7, and miR-320b) are known to have anti-cancer and/or anti-angiogenic activity. These microRNAs were also increased by DHA treatment in the exosomes from other breast cancer lines (MDA-MB-231, ZR751 and BT20), but not in exosomes from normal breast cells (MCF10A). When DHA-treated MCF7 cells were co-cultured with or their exosomes were directly applied to endothelial cell cultures, we observed an increase in the expression of these microRNAs in the endothelial cells. Furthermore, overexpression of miR-23b and miR-320b in endothelial cells decreased the expression of their pro-angiogenic target genes (PLAU, AMOTL1, NRP1 and ETS2) and significantly inhibited tube formation by endothelial cells, suggesting that the microRNAs transferred by exosomes mediate DHA's anti-angiogenic action. These effects could be reversed by knockdown of the Rab GTPase, Rab27A, which controls exosome release. CONCLUSIONS: We conclude that DHA alters breast cancer exosome secretion and microRNA contents, which leads to the inhibition of angiogenesis. Our data demonstrate that breast cancer exosome signaling can be targeted to inhibit tumor angiogenesis and provide new insight into DHA's anticancer action, further supporting its use in cancer therapy.
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Secretion of miRNAs via exosomes is regulated by signaling molecules such as interleukin-4 and docosahexaenoic acid.
“Secretion of miRNAs via exosomes have also been reported to be regulated by signaling molecules, such as interleukin-4 (IL4) (132) and Docosahexaenoic acid (DHA) (133).”
From Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation (2018) · cites this paper as [133]
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- Authors
- Hannafon, B. N., Carpenter, K. J., Berry, W. L., Janknecht, R., Dooley, W. C., & Ding, W.-Q.
- Affiliations
- University of Oklahoma Health Sciences Center (US)
- OU Health Stephenson Cancer Center (US)
- Corresponding author
- Ding, Wei-Qun
- Venue
- Molecular Cancer
- Published
- 2015-07-16
- Volume
- 14
- Issue
- 1
- Pages
- 133-133
- ISSN
- 1476-4598 (ISSN-L)
- PMC
- PMC4504101
- OpenAlex
- W1936353033
- Cited by
- 218
- References
- 50
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 17 · 2023: 20 · 2022: 23 · 2021: 30 · 2020: 26 · 2019: 19 · 2018: 20 · 2017: 26 · 2016: 20 · 2015: 1
- FWCI
- 9.70
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Molecular Cancer (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- American Cancer Society (CNE-117557)
- University of Oklahoma
- Oklahoma Center for the Advancement of Science and Technology (HR14-147)
- Oklahoma Medical Research Foundation
- National Institutes of Health
- University of Oklahoma Health Sciences Center
- Stephenson Cancer Center
- National Institute of General Medical Sciences (U54GM104938)
- National Center for Research Resources (P20RR016478)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- docosahexaenoic acid, exosomal microRNAs, tumor angiogenesis, anti-angiogenic therapy, let-7a, endothelial tube formation, Rab27a, exosome secretion, intercellular communication, MCF-7 cells, MDA-MB-231 cells
- MeSH terms
- rab27 GTP-Binding Proteins, Biological Transport, Breast Neoplasms, Docosahexaenoic Acids, Female, Humans, Reproducibility of Results, Signal Transduction, Gene Expression Regulation, Neoplastic, Neovascularization, Physiologic, Angiogenesis Inhibitors, rab GTP-Binding Proteins, MicroRNAs, Vascular Endothelial Growth Factor A, Endothelial Cells, Cell Line, Tumor, Exosomes, Gene Knockdown Techniques
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