Exosomes derived from gemcitabine-resistant cells transfer malignant phenotypic traits via delivery of miRNA-222-3p
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BACKGROUND: Although gemcitabine-based chemotherapy has been established as a core multimodal therapy for non-small cell lung cancer (NSCLC) treatment, its clinical efficacy remains limited by the development of acquired resistance following tumor metastasis and relapse. In this study, we investigated how gemcitabine-resistant (GR) cells contribute to the development of NSCLC tumor malignancy via exosome-mediated transfer of microRNAs. METHODS: We first studied the mechanism of exosome internalization via PKH-67 staining and an immunofluorescence assay, then confirmed our finding by transmission electron microscopy and western blot analysis. Candidate miRNAs were identified through microarray analysis. Thereafter, RT-PCR, MTS, Transwell and soft agar assays were performed to assess the role of exosomic miR-222-3p in vitro. A 3' untranslated region reporter assay was applied to identify the target of miR-222-3p. A lung metastasis mouse model was constructed to evaluate tumor growth and metastasis in vivo. Finally, clinical samples were used for correlation analysis between exosomic miR-222-3p levels and patients' response to gemcitabine. RESULTS: A549-GR-derived exosomes were internalized by receipt cells via caveolin- and lipid raft-dependent endocytosis, which allowed the transfer of miR-222-3p. Exosomic miR-222-3p enhanced the proliferation, gemcitabine resistance, migration, invasion, and anti-anoikis of parental sensitive cells by directly targeting the promoter of SOCS3. In addition, a higher level of exosomic miR-222-3p in sera usually predicted worse prognosis in NSCLC patients. CONCLUSION: Our data demonstrate that exosomic-miR-222-3p functions as a principal regulator of gemcitabine resistance and malignant characteristics by targeting SOCS3. The exosomic miR-222-3p level in sera may be a potential prognostic biomarker for predicting gemcitabine sensitivity in NSCLC patients.
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In A549-P cells, endocytosis of exosomal miRNAs is mediated by caveolae- and lipid raft-dependent pathways.
“However, another study conducted in A549-P cells showed that endocytosis of exosomal miRNAs is mediated by caveolae- and lipid raft-dependent pathways (143).”
From Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation (2018) · cites this paper as [143]
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- Authors
- Wei, F., Ma, C., Zhou, T., Dong, X., Luo, Q., Geng, L., Ding, L., Zhang, Y., Zhang, L., Li, N., Li, Y., & Liu, Y.
- Affiliations
- First Hospital of Jilin University (CN)
- Academy of Military Medical Sciences (CN)
- Jilin University (CN)
- Corresponding author
- Liu, Yan
- Venue
- Molecular Cancer
- Published
- 2017-07-25
- Volume
- 16
- Issue
- 1
- Pages
- 132-132
- ISSN
- 1476-4598 (ISSN-L)
- PMC
- PMC5526308
- OpenAlex
- W2736949652
- Cited by
- 245
- References
- 52
- Citations by year
- 2026: 11 · 2025: 19 · 2024: 26 · 2023: 25 · 2022: 32 · 2021: 45 · 2020: 43 · 2019: 23 · 2018: 17 · 2017: 4
- FWCI
- 9.72
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-02-17)
- Open access
- gold
- doi.org
- Locations
- Molecular Cancer (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (81301884, 81401883, 81302173)
- Natural Science Foundation of Jilin Province (20140520036JH, 2016041052GH, 20140414027GH, 20160101053JC)
- Jilin University (450060521279)
- China Postdoctoral Science Foundation (2016M590264)
- 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
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- exosomes, gemcitabine resistance, non-small cell lung cancer, miR-222-3p, SOCS3, caveolin-dependent endocytosis, lipid rafts, metastasis, anoikis resistance, cell proliferation and invasion, serum biomarkers, prognostic factors, chemotherapy response
- MeSH terms
- Gemcitabine, Animals, Carcinoma, Non-Small-Cell Lung, Cell Movement, Deoxycytidine, Female, Humans, Lung Neoplasms, Male, Middle Aged, Neoplasm Recurrence, Local, Gene Expression Regulation, Neoplastic, Mice, SCID, 3' Untranslated Regions, MicroRNAs, Cell Line, Tumor, Cell Proliferation, Mice, Exosomes
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