Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2022

01-12-2022 | Ovarian Cancer | Research

miR-18a-5p derived from mesenchymal stem cells-extracellular vesicles inhibits ovarian cancer cell proliferation, migration, invasion, and chemotherapy resistance

Authors: Xiaoying Wang, Lili Jiang, Qifang Liu

Published in: Journal of Translational Medicine | Issue 1/2022

Login to get access

Abstract

Objective

Ovarian cancer (OC) is a major threat to women’s health. Mesenchymal stem cells (MSCs) are key regulators in cellular communication by secreting extracellular vesicles (EVs) that are involved in OC. This study probed into the mechanism of human MSCs derived-EVs (hMSC-EVs) in regulating OC cell growth and chemotherapy resistance.

Methods

hMSCs and EVs were isolated and identified. After adding EVs, the uptake of EVs by OC CAOV3/ES2 cells (for in vitro studies), and cell proliferation, migration, and invasion were detected. Downregulated miRNAs in hMSC-EVs were screened and miR-18a-5p expression in OC patients was detected. The prognosis of OC patients was analyzed. Binding sites of miR-18a-5p and NACC1 were predicted and validated. NACC1 expression in OC tissues was measured by RT-qPCR, and its correlation with miR-18a-5p was analyzed by Pearson method. AKT/mTOR pathway activation was assessed by WB. The cisplatin sensitivity of EVs-treated CAOV3 cells was evaluated via MTT assay and tested by tumor formation assay in nude mice.

Results

hMSC-EVs suppressed OC cell proliferation, migration, and invasion. miR-18a-5p was downregulated in OC and miR-18a-5p low expression was associated with a poor prognosis. EV-encapsulated miR-18a-5p targeted NACC1. NACC1 was upregulated in OC tissues. miR-18a-5p knockdown and NACC1 overexpression both annulled the inhibition of hMSC-EVs on OC cell growth. AKT and mTOR were elevated in OC and NACC1 activated the AKT/mTOR pathway in OC cells. hMSC-EVs promoted cisplatin sensitivity of OC cells by carrying miR-18a-5p.

Conclusion

hMSC-EVs-derived miR-18a-5p inhibits OC cell proliferation, migration, invasion, and chemotherapy resistance.
Appendix
Available only for authorised users
Literature
1.
Kujawa KA, Lisowska KM. Ovarian cancer–from biology to clinic. Postepy Hig Med Dosw (Online). 2015;69:1275–90.CrossRef
2.
Malander S, Hjerpe E, Carlson J, Borg A. Ovarian cancer is in many ways a heterogeneous disease. Lakartidningen. 2015;112:DIUR.PubMed
3.
An Y, Yang Q. Tumor-associated macrophage-targeted therapeutics in ovarian cancer. Int J Cancer. 2021;149:21–30.CrossRefPubMed
4.
Al-Alem LF, Pandya UM, Baker AT, Bellio C, Zarrella BD, Clark J, DiGloria CM, Rueda BR. Ovarian cancer stem cells: what progress have we made? Int J Biochem Cell Biol. 2019;107:92–103.CrossRefPubMed
5.
Ottevanger PB. Ovarian cancer stem cells more questions than answers. Semin Cancer Biol. 2017;44:67–71.CrossRefPubMed
6.
Christie EL, Bowtell DDL. Acquired chemotherapy resistance in ovarian cancer. Ann Oncol. 2017;28:viii13–5.CrossRefPubMed
7.
Gloss BS, Samimi G. Epigenetic biomarkers in epithelial ovarian cancer. Cancer Lett. 2014;342:257–63.CrossRefPubMed
8.
Storti G, Scioli MG, Kim BS, Terriaca S, Fiorelli E, Orlandi A, Cervelli V. Mesenchymal stem cells in adipose tissue and extracellular vesicles in ovarian cancer patients: a bridge toward metastatic diffusion or a new therapeutic opportunity? Cells. 2021;10:2117.CrossRefPubMedPubMedCentral
9.
Yasui T, Paisrisarn P, Yanagida T, Konakade Y, Nakamura Y, Nagashima K, Musa M, Thiodorus IA, Takahashi H, Naganawa T, et al. Molecular profiling of extracellular vesicles via charge-based capture using oxide nanowire microfluidics. Biosens Bioelectron. 2021;194: 113589.CrossRefPubMed
10.
Liu Y, Xia Y, Smollar J, Mao W, Wan Y. The roles of small extracellular vesicles in lung cancer: molecular pathology, mechanisms, diagnostics, and therapeutics. Biochim Biophys Acta Rev Cancer. 2021;1876: 188539.CrossRefPubMed
11.
van Niel G, D’Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19:213–28.CrossRefPubMed
12.
Namee NM, O’Driscoll L. Extracellular vesicles and anti-cancer drug resistance. Biochim Biophys Acta Rev Cancer. 2018;1870:123–36.CrossRefPubMed
13.
Ela S, Mager I, Breakefield XO, Wood MJ. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov. 2013;12:347–57.CrossRef
14.
Xie C, Ji N, Tang Z, Li J, Chen Q. The role of extracellular vesicles from different origin in the microenvironment of head and neck cancers. Mol Cancer. 2019;18:83.CrossRefPubMedPubMedCentral
15.
Kahmini FR, Shahgaldi S. Therapeutic potential of mesenchymal stem cell-derived extracellular vesicles as novel cell-free therapy for treatment of autoimmune disorders. Exp Mol Pathol. 2021;118: 104566.CrossRefPubMed
16.
Touboul C, Vidal F, Pasquier J, Lis R, Rafii A. Role of mesenchymal cells in the natural history of ovarian cancer: a review. J Transl Med. 2014;12:271.CrossRefPubMedPubMedCentral
17.
Wan FZ, Chen KH, Sun YC, Chen XC, Liang RB, Chen L, Zhu XD. Exosomes overexpressing miR-34c inhibit malignant behavior and reverse the radioresistance of nasopharyngeal carcinoma. J Transl Med. 2020;18:12.CrossRefPubMedPubMedCentral
18.
Gomes JPA, Assoni AF, Pelatti M, Coatti G, Okamoto OK, Zatz M. Deepening a simple question: can MSCs be used to treat cancer? Anticancer Res. 2017;37:4747–58.PubMed
19.
Mader EK, Butler G, Dowdy SC, Mariani A, Knutson KL, Federspiel MJ, Russell SJ, Galanis E, Dietz AB, Peng KW. Optimizing patient derived mesenchymal stem cells as virus carriers for a phase I clinical trial in ovarian cancer. J Transl Med. 2013;11:20.CrossRefPubMedPubMedCentral
20.
de Araujo FV, O’Valle F, Serrano-Saenz S, Anderson P, Andres E, Lopez-Penalver J, Tovar I, Nieto A, Santos A, Martin F, et al. Exosomes derived from mesenchymal stem cells enhance radiotherapy-induced cell death in tumor and metastatic tumor foci. Mol Cancer. 2018;17:122.CrossRef
21.
Gatti S, Bruno S, Deregibus MC, Sordi A, Cantaluppi V, Tetta C, Camussi G. Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia-reperfusion-induced acute and chronic kidney injury. Nephrol Dial Transplant. 2011;26:1474–83.CrossRefPubMed
22.
Figueroa J, Phillips LM, Shahar T, Hossain A, Gumin J, Kim H, Bean AJ, Calin GA, Fueyo J, Walters ET, et al. Exosomes from glioma-associated mesenchymal stem cells increase the tumorigenicity of glioma stem-like cells via transfer of miR-1587. Cancer Res. 2017;77:5808–19.CrossRefPubMedPubMedCentral
23.
Mohr A, Zwacka R. The future of mesenchymal stem cell-based therapeutic approaches for cancer - from cells to ghosts. Cancer Lett. 2018;414:239–49.CrossRefPubMed
24.
Bu S, Wang Q, Zhang Q, Sun J, He B, Xiang C, Liu Z, Lai D. Human endometrial mesenchymal stem cells exhibit intrinsic anti-tumor properties on human epithelial ovarian cancer cells. Sci Rep. 2016;6:37019.CrossRefPubMedPubMedCentral
25.
Nishikawa G, Kawada K, Nakagawa J, Toda K, Ogawa R, Inamoto S, Mizuno R, Itatani Y, Sakai Y. Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression via CCR5. Cell Death Dis. 2019;10:264.CrossRefPubMedPubMedCentral
26.
Yuan Z, Kolluri KK, Gowers KH, Janes SM. TRAIL delivery by MSC-derived extracellular vesicles is an effective anticancer therapy. J Extracell Vesicles. 2017;6:1265291.CrossRefPubMedPubMedCentral
27.
28.
Keshtkar S, Azarpira N, Ghahremani MH. Mesenchymal stem cell-derived extracellular vesicles: novel frontiers in regenerative medicine. Stem Cell Res Ther. 2018;9:63.CrossRefPubMedPubMedCentral
29.
Naqvi AR, Slots J. Human and herpesvirus microRNAs in periodontal disease. Periodontol. 2000;2021(87):325–39.
30.
Tang S, Li S, Liu T, He Y, Hu H, Zhu Y, Tang S, Zhou H. MicroRNAs: Emerging oncogenic and tumor-suppressive regulators, biomarkers and therapeutic targets in lung cancer. Cancer Lett. 2021;502:71–83.CrossRefPubMed
31.
Thody J, Moulton V, Mohorianu I. PAREameters: a tool for computational inference of plant miRNA-mRNA targeting rules using small RNA and degradome sequencing data. Nucleic Acids Res. 2020;48:2258–70.CrossRefPubMedPubMedCentral
32.
Lou G, Song X, Yang F, Wu S, Wang J, Chen Z, Liu Y. Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma. J Hematol Oncol. 2015;8:122.CrossRefPubMedPubMedCentral
33.
Rodriguez-Aguayo C, Monroig PDC, Redis RS, Bayraktar E, Almeida MI, Ivan C, Fuentes-Mattei E, Rashed MH, Chavez-Reyes A, Ozpolat B, et al. Regulation of hnRNPA1 by microRNAs controls the miR-18a-K-RAS axis in chemotherapy-resistant ovarian cancer. Cell Discov. 2017;3:17029.CrossRefPubMedPubMedCentral
34.
Gao M, Herlinger AL, Wu R, Wang TL, Shih IM, Kong B, Rangel LBA, Yang JM. NAC1 attenuates BCL6 negative autoregulation and functions as a BCL6 coactivator of FOXQ1 transcription in cancer cells. Aging (Albany NY). 2020;12:9275–91.CrossRef
35.
Du W, Feng Z, Sun Q. LncRNA LINC00319 accelerates ovarian cancer progression through miR-423-5p/NACC1 pathway. Biochem Biophys Res Commun. 2018;507:198–202.CrossRefPubMed
36.
Zhang J, Wang L, Jiang J, Qiao Z. The lncRNA SNHG15/miR-18a-5p axis promotes cell proliferation in ovarian cancer through activating Akt/mTOR signaling pathway. J Cell Biochem. 2020;121:4699–710.CrossRefPubMed
37.
Ahn SY, Sung DK, Kim YE, Sung S, Chang YS, Park WS. Brain-derived neurotropic factor mediates neuroprotection of mesenchymal stem cell-derived extracellular vesicles against severe intraventricular hemorrhage in newborn rats. Stem Cells Transl Med. 2021;10:374–84.CrossRefPubMed
38.
Jing T, Liao J, Shen K, Chen X, Xu Z, Tian W, Wang Y, Jin B, Pan H. Protective effect of urolithin a on cisplatin-induced nephrotoxicity in mice via modulation of inflammation and oxidative stress. Food Chem Toxicol. 2019;129:108–14.CrossRefPubMed
39.
Ozkok A, Ravichandran K, Wang Q, Ljubanovic D, Edelstein CL. NF-kappaB transcriptional inhibition ameliorates cisplatin-induced acute kidney injury (AKI). Toxicol Lett. 2016;240:105–13.CrossRefPubMed
40.
Wang H, Xiong Y, Wang R, Yu Y, Wang J, Hu Z, Sun C, Tu J, He D. Cisplatin-stitched alpha-poly(glutamatic acid) nanoconjugate for enhanced safety and effective tumor inhibition. Eur J Pharm Sci. 2018;119:189–99.CrossRefPubMed
41.
Quinones-Diaz BI, Reyes-Gonzalez JM, Sanchez-Guzman V, Conde-Del Moral I, Valiyeva F, Santiago-Sanchez GS, Vivas-Mejia PE. MicroRNA-18a-5p suppresses tumor growth via targeting matrix metalloproteinase-3 in cisplatin-resistant ovarian cancer. Front Oncol. 2020;10: 602670.CrossRefPubMedPubMedCentral
42.
Fu C, Yuan M, Sun J, Liu G, Zhao X, Chang W, Ma Z. RNA-binding Motif protein 11 (RBM11) serves as a prognostic biomarker and promotes ovarian cancer progression. Dis Markers. 2021;2021:3037337.PubMedPubMedCentral
43.
Webb PM, Jordan SJ. Epidemiology of epithelial ovarian cancer. Best Pract Res Clin Obstet Gynaecol. 2017;41:3–14.CrossRefPubMed
44.
Khalil C, Moussa M, Azar A, Tawk J, Habbouche J, Salameh R, Ibrahim A, Alaaeddine N. Anti-proliferative effects of mesenchymal stem cells (MSCs) derived from multiple sources on ovarian cancer cell lines: an in-vitro experimental study. J Ovarian Res. 2019;12:70.CrossRefPubMedPubMedCentral
45.
O’Brien KP, Khan S, Gilligan KE, Zafar H, Lalor P, Glynn C, O’Flatharta C, Ingoldsby H, Dockery P, De Bhulbh A, et al. Employing mesenchymal stem cells to support tumor-targeted delivery of extracellular vesicle (EV)-encapsulated microRNA-379. Oncogene. 2018;37:2137–49.CrossRefPubMed
46.
Li P, Xin H, Lu L. Extracellular vesicle-encapsulated microRNA-424 exerts inhibitory function in ovarian cancer by targeting MYB. J Transl Med. 2021;19:4.CrossRefPubMedPubMedCentral
47.
Chen Q, Rutten V, Cheng WT, Tong M, Wei J, Stone P, Ching LM, Chamley LW. Phagocytosis of extracellular vesicles extruded from the placenta by ovarian cancer cells inhibits growth of the cancer cells. Int J Gynecol Cancer. 2018;28:545–52.CrossRefPubMed
48.
Ghafouri-Fard S, Shoorei H, Taheri M. miRNA profile in ovarian cancer. Exp Mol Pathol. 2020;113: 104381.CrossRefPubMed
49.
Staicu CE, Predescu DV, Rusu CM, Radu BM, Cretoiu D, Suciu N, Cretoiu SM, Voinea SC. Role of microRNAs as clinical cancer biomarkers for ovarian cancer: a short overview. Cells. 2020;9:169.CrossRefPubMedCentral
50.
Zhao Y, Liu XL, Huang JH, Yin AJ, Zhang H. MicroRNA-18a suppresses ovarian carcinoma progression by targeting CBX7 and regulating ERK/MAPK signaling pathway and epithelial-to-mesenchymal transition. Eur Rev Med Pharmacol Sci. 2020;24:5292–302.PubMed
51.
Reza A, Choi YJ, Yasuda H, Kim JH. Human adipose mesenchymal stem cell-derived exosomal-miRNAs are critical factors for inducing anti-proliferation signalling to A2780 and SKOV-3 ovarian cancer cells. Sci Rep. 2016;6:38498.CrossRefPubMedPubMedCentral
52.
Wang L, Yin P, Wang J, Wang Y, Sun Z, Zhou Y, Guan X. Delivery of mesenchymal stem cells-derived extracellular vesicles with enriched miR-185 inhibits progression of OPMD. Artif Cells Nanomed Biotechnol. 2019;47:2481–91.CrossRefPubMed
53.
Hu G, Xia Y, Zhang J, Chen Y, Yuan J, Niu X, Zhao B, Li Q, Wang Y, Deng Z. ESC-sEVs rejuvenate senescent hippocampal nscs by activating lysosomes to improve cognitive dysfunction in vascular dementia. Adv Sci (Weinh). 2020;7:1903330.CrossRef
54.
55.
Nakayama N, Kato H, Sakashita G, Nariai Y, Nakayama K, Kyo S, Urano T. Protein complex formation and intranuclear dynamics of NAC1 in cancer cells. Arch Biochem Biophys. 2016;606:10–5.CrossRefPubMed
56.
Zhang Y, Cheng Y, Ren X, Zhang L, Yap KL, Wu H, Patel R, Liu D, Qin ZH, Shih IM, Yang JM. NAC1 modulates sensitivity of ovarian cancer cells to cisplatin by altering the HMGB1-mediated autophagic response. Oncogene. 2012;31:1055–64.CrossRefPubMed
57.
Nakayama K, Rahman MT, Rahman M, Yeasmin S, Ishikawa M, Katagiri A, Iida K, Nakayama N, Miyazaki K. Biological role and prognostic significance of NAC1 in ovarian cancer. Gynecol Oncol. 2010;119:469–78.CrossRefPubMed
58.
Gao M, Wu RC, Herlinger AL, Yap K, Kim JW, Wang TL, Shih Ie M. Identification of the NAC1-regulated genes in ovarian cancer. Am J Pathol. 2014;184:133–40.CrossRefPubMedPubMedCentral
59.
Li H, Zeng J, Shen K. PI3K/AKT/mTOR signaling pathway as a therapeutic target for ovarian cancer. Arch Gynecol Obstet. 2014;290:1067–78.CrossRefPubMed
60.
Mabuchi S, Kuroda H, Takahashi R, Sasano T. The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer. Gynecol Oncol. 2015;137:173–9.CrossRefPubMed
61.
Zhang S, Leng T, Zhang Q, Zhao Q, Nie X, Yang L. Sanguinarine inhibits epithelial ovarian cancer development via regulating long non-coding RNA CASC2-EIF4A3 axis and/or inhibiting NF-kappaB signaling or PI3K/AKT/mTOR pathway. Biomed Pharmacother. 2018;102:302–8.CrossRefPubMed
62.
Zhang X, Qin T, Zhu Z, Hong F, Xu Y, Zhang X, Xu X, Ma A. Ivermectin augments the in vitro and in vivo efficacy of cisplatin in epithelial ovarian cancer by suppressing Akt/mTOR signaling. Am J Med Sci. 2020;359:123–9.CrossRefPubMed
63.
Li L, Yu H, Ren Q. MiR-218-5p suppresses the progression of retinoblastoma through targeting NACC1 and inhibiting the AKT/mTOR signaling pathway. Cancer Manag Res. 2020;12:6959–67.CrossRefPubMedPubMedCentral
64.
Cao Z, Chen H, Mei X, Li X. Silencing of NACC1 inhibits the proliferation, migration and invasion of nasopharyngeal carcinoma cells via regulating the AKT/mTOR signaling pathway. Oncol Lett. 2021;22:828.CrossRefPubMedPubMedCentral
65.
Han J, Qu H, Han M, Ding Y, Xie M, Hu J, Chen Y, Dong H. MSC-induced lncRNA AGAP2-AS1 promotes stemness and trastuzumab resistance through regulating CPT1 expression and fatty acid oxidation in breast cancer. Oncogene. 2021;40:833–47.CrossRefPubMed
66.
67.
Uhr K, van der Smissen WJCP, Heine AAJ, Ozturk B, van Jaarsveld MTM, Boersma AWM, Jager A, Wiemer EAC, Smid M, Foekens JA, Martens JWM. MicroRNAs as possible indicators of drug sensitivity in breast cancer cell lines. PLoS ONE. 2019;14: e0216400.CrossRefPubMedPubMedCentral
68.
Zheng P, Dong L, Zhang B, Dai J, Zhang Y, Wang Y, Qin S. Long noncoding RNA CASC2 promotes paclitaxel resistance in breast cancer through regulation of miR-18a-5p/CDK19. Histochem Cell Biol. 2019;152:281–91.CrossRefPubMed
Metadata
Title
miR-18a-5p derived from mesenchymal stem cells-extracellular vesicles inhibits ovarian cancer cell proliferation, migration, invasion, and chemotherapy resistance
Authors
Xiaoying Wang
Lili Jiang
Qifang Liu
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2022
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-022-03422-7

Other articles of this Issue 1/2022

Journal of Translational Medicine 1/2022 Go to the issue

Review

Efficacy and safety of novel oral anticoagulants in patients with atrial nonvalvular atrial fibrillation and diabetes mellitus: a systematic review and meta-analysis

Research

LPAR5 confers radioresistance to cancer cells associated with EMT activation via the ERK/Snail pathway

Research

A randomized controlled trial of the influence of yoga for women with symptoms of post-traumatic stress disorder

Research

Synergistic effect of the commonest residual risk factors, remnant cholesterol, lipoprotein(a), and inflammation, on prognosis of statin-treated patients with chronic coronary syndrome

Research

Genome-wide profiling of retroviral DNA integration and its effect on clinical pre-infusion CAR T-cell products

Research

Ground truth labels challenge the validity of sepsis consensus definitions in critical illness
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits