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Cancer Cell International
Published in: Cancer Cell International 1/2024

Open Access 01-12-2024 | Kidney Cancer | Research

Exosome-mediated secretion of miR-127-3p regulated by RAB27A accelerates metastasis in renal cell carcinoma

Authors: Dae Hyun Song, Jong Sil Lee, Jeong-Hee Lee, Dong Chul Kim, Jung Wook Yang, Min Hye Kim, Ji Min Na, Hyun-kyung Cho, Jiyun Yoo, Hyo Jung An

Published in: Cancer Cell International | Issue 1/2024

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Abstract

Background

The exosome-mediated extracellular secretion of miRNAs occurs in many cancers, and RAB27A is a potent regulator of exosome secretion. For metastatic renal cell carcinoma (RCC), this study examines the mechanisms of cancer metastasis via the RAB27A-regulated secretion of specific miRNAs.

Methods

RAB27A knockdown (KD) and overexpressing (OE) RCC cells were used to examine cell migration and adhesion. The particle counts and sizes of exosomes in RAB27A OE cells were analyzed using Exoview, and those of intraluminal vesicles (ILV) and multivesicular bodies (MVB) were measured using an electron microscope. Analysis of RNA sequences, protein–protein interaction networks, and the competing endogenous RNA (ceRNA) network were used to identify representative downregulated miRNAs that are likely to undergo cargo-sorting into exosomes and subsequent secretion. A molecular beacon of miR-137-3p, one of the most representatively downregulated genes with a fold change of 339, was produced, and its secretion was analyzed using Exoview. RAB27A OE and control cells were incubated in an exosome-containing media to determine the uptake of tumor suppressor miRNAs that affect cancer cell metastasis.

Results

Migration and cell adhesion were higher in RAB27A OE cells than in RAB27A KD cells. Electron microscopy revealed that the numbers of multivesicular bodies and intraluminal vesicles per cell were higher in RAB27A OE cells than in control cells, suggesting their secretion. The finding revealed that miR-127-3p was sorted into exosomes and disposed of extracellularly. Protein–protein interaction analysis revealed MYCN to be the most significant hub for RAB27A-OE RCC cells. ceRNA network analysis revealed that MAPK4 interacted strongly with miR-127-3p.

Conclusion

The disposal of miR-127-3p through exosome secretion in RAB27A overexpressing cells may not inhibit the MAPK pathway to gain metastatic potential by activating MYCN. The exosomes containing miRNAs are valuable therapeutic targets for cancer treatment.
Appendix
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Literature
1.
2.
Siegler EL, Kim YJ, Wang P. Nanomedicine targeting the tumor microenvironment: therapeutic strategies to inhibit angiogenesis, remodel matrix, and modulate immune responses. J Cell Immunother. 2016;2:69–78.CrossRef
3.
Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9:654–9.PubMedCrossRef
4.
5.
Chen X, Liang H, Zhang J, Zen K, Zhang C. Secreted microRNAs: a new form of intercellular communication. Trends Cell Biol. 2012;22:125–32.PubMedCrossRef
6.
Sadik N, Cruz L, Gurtner A, Rodosthenous RS, et al. Extracellular RNAs: a new awareness of old perspectives. Extracellular RNA. 2018;1:1–15.
7.
Ghayad SE, Rammal G, Ghamloush F, Basma H, et al. Exosomes derived from embryonal and alveolar rhabdomyosarcoma carry differential miRNA cargo and promote invasion of recipient fibroblasts. Sci Rep. 2016;6:1–15.CrossRef
8.
9.
Nolte-’t Hoen E, Cremer T, Gallo RC, Margolis LB. Extracellular vesicles and viruses: are they close relatives? Proc Natl Acad Sci USA. 2016;113:9155–61.PubMedPubMedCentralCrossRef
10.
Mirzaei H, Sahebkar A, Jaafari MR, Goodarzi M, Mirzaei HR. Diagnostic and therapeutic potential of exosomes in cancer: the beginning of a new tale? J Cell Physiol. 2017;232:3251–60.PubMedCrossRef
11.
12.
Melman YF, Shah R, Danielson K, Xiao J, Simonson B, et al. Circulating MicroRNA-30d is associated with response to cardiac resynchronization therapy in heart failure and regulates cardiomyocyte apoptosis: a translational pilot study. Circulation. 2015;131:2202–16.PubMedPubMedCentralCrossRef
13.
Cui S, Cheng Z, Qin W, Jiang L. Exosomes as a liquid biopsy for lung cancer. Lung Cancer. 2018;116:46–54.PubMedCrossRef
14.
Dong W, Cui J, Yang J, Li W, et al. Decreased expression of Rab27A and Rab27B correlates with metastasis and poor prognosis in colorectal cancer. Discov Med. 2015;20:357–67.PubMed
15.
Dong WW, Mou Q, Chen J, Cui JT, et al. Differential expression of Rab27A/B correlates with clinical outcome in hepatocellular carcinoma. World J Gastroenterol. 2012;18:1806–13.PubMedPubMedCentralCrossRef
16.
Koh HM, Song DH. Prognostic role of Rab27A and Rab27B expression in patients with non-small cell lung carcinoma. Thoracic cancer. 2019;10:143–9.PubMedCrossRef
17.
Ren P, Yang X, Zhai X, Zhang Y, Huang J. Overexpression of Rab27B is correlated with distant metastasis and poor prognosis in ovarian cancer. Oncol Lett. 2016;12:1539–45.PubMedPubMedCentralCrossRef
18.
Zhao H, Wang Q, Wang X, Zhu H, Zhang S, et al. Correlation Between RAB27B and p53 Expression and Overall Survival in Pancreatic Cancer. Pancreas. 2016;45:204–10.PubMedCrossRef
19.
Mathieu M, Martin-Jaular L, Lavieu G, Théry C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol. 2019;21:9–17.PubMedCrossRef
20.
Fukuda M. Regulation of secretory vesicle traffic by Rab small GTPases. Cell Mol Life Sci. 2008;65:2801–13.PubMedCrossRef
21.
22.
Seabra MC, Mules EH, Hume AN. Rab GTPases, intracellular traffic and disease. Trends Mol Med. 2002;8:23–30.PubMedCrossRef
23.
Hutagalung AH, Novick PJ. Role of Rab GTPases in membrane traffic and cell physiology. Physiol Rev. 2011;91:119–49.PubMedCrossRef
24.
Ostrowski M, Carmo NB, Krumeich S, et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol. 2010;12:19–30.PubMedCrossRef
25.
26.
Ostenfeld MS, Jeppesen DK, Laurberg JR, Boysen AT, et al. Cellular disposal of miR23b by RAB27-dependent exosome release is linked to acquisition of metastatic properties. Cancer Res. 2014;74:5758–71.PubMedCrossRef
27.
Alvarez-Garcia I, Miska EA. MicroRNA functions in animal development and human disease. 2005.
28.
Krek A, Grün D, Poy MN, Wolf R, et al. Combinatorial microRNA target predictions. Nat Genet. 2005;37:495–500.PubMedCrossRef
29.
Villarroya-Beltri C, Baixauli F, Gutiérrez-Vázquez C, et al. Sorting it out: regulation of exosome loading. In Seminars in cancer biology. 2014;28:3–13.CrossRef
30.
Villarroya-Beltri C, Gutiérrez-Vázquez C, et al. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun. 2013;4:1–10.CrossRef
31.
An HJ, Song DH, Koh HM, Ko GH, et al. RAB27A is an independent prognostic factor in clear cell renal cell carcinoma. Biomark Med. 2019;13:239–47.PubMedCrossRef
32.
Zhang Z, Qian W, Wang S, Ji D, Wang Q, et al. Analysis of lncRNA-associated ceRNA network reveals potential lncRNA biomarkers in human colon adenocarcinoma. Cell Physiol Biochem. 2018;49:1778–91.PubMedCrossRef
33.
Baker MB, Bao G, Searles CD. In vitro quantification of specific microRNA using molecular beacons. Nucleic Acids Res. 2012;40:e13.PubMedCrossRef
34.
Obernosterer G, Martinez J, Alenius M. Locked nucleic acid-based in situ detection of microRNAs in mouse tissue sections. Nat Protoc. 2007;2:1508–14.PubMedCrossRef
35.
Bierings R, Hellen N, Kiskin N, Knipe L, et al. The interplay between the Rab27A effectors Slp4-a and MyRIP controls hormone-evoked Weibel-Palade body exocytosis. Blood. 2012;120:2757–67.PubMedPubMedCentralCrossRef
36.
Niu H, Bihui HY, Dalla-Favera R. Antigen receptor signaling induces MAP kinase-mediated phosphorylation and degradation of the BCL-6 transcription factor. Genes Dev. 1998;12:1953–61.PubMedPubMedCentralCrossRef
37.
Saito M, Ota Y, Ohashi H, Dei Y, et al. CD40-CD40 ligand signal induces the intercellular adhesion molecule-1 expression through nuclear factor-kappa B p50 in cultured salivary gland epithelial cells from patients with Sjögren’s syndrome. Mod Rheumatol. 2007;17:45–53.PubMedCrossRef
38.
39.
Zhang X, Guo X, Zhuo R, Tao Y, et al. BRD4 inhibitor MZ1 exerts anti-cancer effects by targeting MYCN and MAPK signaling in neuroblastoma. Biochem Biophys Res Commun. 2022;604:63–9.PubMedCrossRef
40.
Eleveld TF, Schild L, Koster J, Zwijnenburg DA, et al. RAS–MAPK pathway-driven tumor progression is associated with loss of CIC and other genomic aberrations in neuroblastomanovel mutations drive the RAS–MAPK pathway in neuroblastoma. Cancer Res. 2018;78:6297–307.PubMedCrossRef
41.
Chen Y, Xu L, Mayakonda A, Huang M, et al. Bromodomain and extraterminal proteins foster the core transcriptional regulatory programs and confer vulnerability in liposarcoma. Nat Commun. 2019;10:1353.PubMedPubMedCentralCrossRef
42.
Whitehead KA, Langer R, Anderson DG. Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discovery. 2009;8:129–38.PubMedCrossRef
43.
44.
Bang C, Thum T. Exosomes: new players in cell–cell communication. Int J Biochem Cell Biol. 2012;44:2060–4.PubMedCrossRef
45.
Camussi G, Deregibus MC, Bruno S, Cantaluppi V, Biancone L. Exosomes/microvesicles as a mechanism of cell-to-cell communication. Kidney Int. 2010;78:838–48.PubMedCrossRef
46.
47.
Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367:6977.CrossRef
48.
Gurunathan S, Kang M, Jeyaraj M, et al. Review of the isolation, characterization, biological function, and multifarious therapeutic approaches of exosomes. Cells. 2019;8:307.PubMedPubMedCentralCrossRef
Metadata
Title
Exosome-mediated secretion of miR-127-3p regulated by RAB27A accelerates metastasis in renal cell carcinoma
Authors
Dae Hyun Song
Jong Sil Lee
Jeong-Hee Lee
Dong Chul Kim
Jung Wook Yang
Min Hye Kim
Ji Min Na
Hyun-kyung Cho
Jiyun Yoo
Hyo Jung An
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2024
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-024-03334-0

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