Exosomal miR-21-5p derived from gastric cancer promotes peritoneal metastasis via mesothelial-to-mesenchymal transition
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Peritoneal metastasis is a primary metastatic route for gastric cancers, and the mechanisms underlying this process are still unclear. Peritoneal mesothelial cells (PMCs) undergo mesothelial-to-mesenchymal transition (MMT) to provide a favorable environment for metastatic cancer cells. In this study, we investigated how the exosomal miR-21-5p induces MMT and promotes peritoneal metastasis. Gastric cancer (GC)-derived exosomes were identified by transmission electron microscopy and western blot analysis, then the uptake of exosomes was confirmed by PKH-67 staining. The expression of miR-21-5p and SMAD7 were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot, and the interactions between miR-21-5p and its target genes SMAD7 were confirmed by Luciferase reporter assays. The MMT of PMCs was determined by invasion assays, adhesion assays, immunofluorescent assay, and western blot. Meanwhile, mouse model of tumor peritoneal dissemination model was performed to investigate the role of exosomal miR-21-5p in peritoneal metastasis in vivo. We found that PMCs could internalize GC-derived exosomal miR-21-5p and led to increased levels of miR-21-5p in PMCs. Through various types of in vitro and in vivo assays, we confirmed that exosomal miR-21-5p was able to induce MMT of PMCs and promote tumor peritoneal metastasis. Moreover, our study revealed that this process was promoted by exosomal miR-21-5p through activating TGF-β/Smad pathway via targeting SMAD7. Altogether, our data suggest that exosomal miR-21-5p induces MMT of PMCs and promote cancer peritoneal dissemination by targeting SMAD7. The exosomal miR-21-5p may be a novel therapeutic target for GC peritoneal metastasis.
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microRNA's presence in exosomes has been reported in different cells and cancer types.
“microRNA's presence in exosomes have been already reported in different cells and cancer types (44–50).”
From Potential Therapeutic Effects of Exosomes Packed With a miR-21-Sponge Construct in a Rat Model of Glioblastoma (2019) · cites this paper as [47]
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- Authors
- Li, Q., Li, B., Li, Q., Wei, S., He, Z., Huang, X., Wang, L., Xia, Y., Xu, Z., Li, Z., Wang, W., Yang, L., Zhang, D., & Xu, Z.
- Affiliations
- Jiangsu Province Hospital (CN)
- Corresponding author
- Zhang, Diancai
- ORCID
- Venue
- Cell Death & Disease
- Published
- 2018-08-28
- Volume
- 9
- Issue
- 9
- Pages
- 854-854
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC6113299
- OpenAlex
- W2889190369
- Cited by
- 219
- References
- 47
- Citations by year
- 2026: 11 · 2025: 21 · 2024: 31 · 2023: 34 · 2022: 45 · 2021: 46 · 2020: 17 · 2019: 14
- FWCI
- 7.03
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Natural Science Foundation of China (JX10231801, 30901443)
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD, JX10231801, JX 10231801)
- National Institutes of Health
- 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
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- gastric cancer, peritoneal carcinomatosis, exosomes, miR-21-5p, mesothelial-to-mesenchymal transition, peritoneal mesothelial cells, Smad7, TGF-β/Smad signaling, extracellular vesicles, tumor microenvironment
- MeSH terms
- Animals, Cell Movement, Epithelium, Female, Humans, Male, Mice, Nude, Middle Aged, Neoplasm Metastasis, Peritoneal Neoplasms, Peritoneum, Stomach Neoplasms, Signal Transduction, Gene Expression Regulation, Neoplastic, Transforming Growth Factor beta, MicroRNAs, Cell Line, Tumor, Cell Proliferation, Mice, Smad7 Protein, Exosomes, Epithelial-Mesenchymal Transition
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