IMR Press / FBL / Volume 27 / Issue 9 / DOI: 10.31083/j.fbl2709256
Open Access Original Research
Targeting Castration-Resistant Prostate Cancer Using Mesenchymal Stem Cell Exosomes for Therapeutic MicroRNA-let-7c Delivery
Ida Kurniawati1,2,†Ming-Che Liu3,4,5,6,7,8,†Chia-Ling Hsieh9,10Anh Duy Do1,11Shian-Ying Sung1,4,5,7,8,9,12,*
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1 International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, 110 Taipei, Taiwan
2 Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, 110 Taipei, Taiwan
3 Department of Urology, Taipei Medical University Hospital, 110 Taipei, Taiwan
4 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 110 Taipei, Taiwan
5 Clinical Research Center, Taipei Medical University Hospital, 110 Taipei, Taiwan
6 School of Dental Technology, College of Oral Medicine, Taipei Medical University, 110 Taipei, Taiwan
7 Office of Human Research, Taipei Medical University, 110 Taipei, Taiwan
8 TMU-Research Center for Urology and Kidney, Taipei Medical University, 110 Taipei, Taiwan
9 The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, 110 Taipei, Taiwan
10 Laboratory of Translational Medicine, Development Center for Biotechnology, 115 Taipei, Taiwan
11 Department of Physiology, Pathophysiology and Immunology, Pham Ngoc Thach University of Medicine, 700000 Ho Chi Minh City, Vietnam
12 TMU Research Center for Cancer Translational Medicine, Taipei Medical University, 110 Taipei, Taiwan
*Correspondence: ssung@tmu.edu.tw (Shian-Ying Sung)
These authors contributed equally.
Academic Editors: Antonio Barbieri and Francesca Bruzzese
Front. Biosci. (Landmark Ed) 2022, 27(9), 256; https://doi.org/10.31083/j.fbl2709256
Submitted: 29 June 2022 | Revised: 3 August 2022 | Accepted: 15 August 2022 | Published: 6 September 2022
(This article belongs to the Special Issue New Insights against Cancer Progression and Metastasis)
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.
Abstract

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.

Keywords
castration-resistant prostate cancer
mesenchymal stem cell
exosome
microRNA-let-7c
tumor microenvironment
Figures
Fig. 1.
Funding
108-TMUH-SP-01/ Taipei Medical University Hospital
MOST 110-2314-B-038-136/ Ministry of Education (MOE), Ministry of Science and Technology
MOST 110-2314-B-038-137-MY3/ Ministry of Education (MOE), Ministry of Science and Technology
MOST 111-2314-B-169-001/ Ministry of Education (MOE), Ministry of Science and Technology
MOHW110-TDU-B-212-124007/ Ministry of Health and Welfare
MOHW110-B-212-144026/ Ministry of Health and Welfare
MOHW111-TDU-B-221-114002/ Ministry of Health and Welfare
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