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Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
Targeting Castration-Resistant Prostate Cancer Using Mesenchymal Stem Cell Exosomes for Therapeutic MicroRNA-let-7c
Ida Kurniawati1,2, Ming-Che Liu3,4,5,6,7,8, Chia-Ling Hsieh9,10
1International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, 110 Taipei, Taiwan.
Background:
Castration-resistant prostate cancer (PCa; CRPC) has a poor response to androgen deprivation therapy and is considered an incurable disease. MicroRNA (miR)-lethal 7c (let-7c) was implied to be a tumor suppressor in PCa, and treatment with exogenous let-7c targets both cancer cells and their associated mesenchymal stem cells (MSCs) to prevent CRPC progression and metastasis. Exosomes are nanometer-sized membrane-bound vesicles which have an absolute predominance in biocompatibility for drug delivery and gene therapy by mediating cell-to-cell communication. By utilizing the intrinsic tumor-targeting property of MSCs, this study aimed to investigate the feasibility of MSC-derived exosomes as an exogenous miR delivery system to target CRPC, using miR let-7c as an example.
Methods:
Bioinformatics analysis was performed to observe miR-let-7c expression in clinical samples by utilizing the GEO database. MSC-derived exosomes were collected from a human bone marrow-derived MSC cell line after cell transfection with either a pre-miR negative control or pre-miR-let-7c, and further characterized through nanoparticle tracking analysis and Western blotting. miR-let-7c expression was determined using RT-qPCR, and the phenotypic effects of both naked and MSC-exosome-encapsulated let-7c on CRPC cells (PC3 and CWR22Rv1) were determined by WST-1 cell proliferation assay and wound healing migration assay.
Results:
miR-let-7c was downregulated in metastatic PCa and high grade group patients. miR-let-7c expression was confirmed to be downregulated in PCa cell lines, with massively decreased in most metastatic CRPC-like cells. Exogenous miR-let-7c can be successfully packaged into MSC exosomes. Treatment with either naked or MSC-exosome-encapsulated miR-let-7c resulted in significant reductions in cell proliferation and migration in CRPC-like PC3 and CWR22Rv1 cells.
Conclusions:
MSC-derived exosomes could serve as a therapeutic let-7c delivery system to target CRPC.
Insights
Mesenchymal stem cell-derived exosomes effectively deliver microRNA let-7c to target castration-resistant prostate cancer cells. This approach shows promise for treating advanced prostate cancer by reducing tumor cell proliferation and migration.
Area of Science:
- Oncology
- Biotechnology
- Gene Therapy
Background:
- Castration-resistant prostate cancer (CRPC) is largely incurable with current therapies.
- MicroRNA let-7c (let-7c) acts as a tumor suppressor in prostate cancer (PCa).
- Exosomes offer a biocompatible platform for drug and gene delivery, mediating cell-to-cell communication.
Purpose of the Study:
- To investigate the potential of mesenchymal stem cell (MSC)-derived exosomes as a delivery system for exogenous let-7c.
- To target CRPC progression and metastasis using MSC-derived exosomes carrying let-7c.
- To evaluate the therapeutic feasibility of this novel delivery system for CRPC.
Main Methods:
- Bioinformatics analysis of let-7c expression in clinical PCa samples using the GEO database.
- Isolation and characterization of MSC-derived exosomes engineered to carry pre-miR-let-7c.
- Assessment of let-7c's impact on CRPC cell proliferation and migration in vitro.
Main Results:
- let-7c expression was significantly downregulated in metastatic PCa and high-grade tumors.
- Engineered MSC exosomes successfully encapsulated and delivered exogenous let-7c.
- Treatment with let-7c, delivered via exosomes or naked, reduced CRPC cell proliferation and migration.
Conclusions:
- MSC-derived exosomes represent a viable therapeutic delivery system for let-7c in CRPC.
- This exosome-based strategy holds potential for inhibiting CRPC progression and metastasis.
- Further research into exosome-mediated gene therapy for CRPC is warranted.
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