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

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

doi:10.1186/s12935-024-03334-0

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

Cancer Cell Int. 2024 Apr 29;24(1):153. doi: 10.1186/s12935-024-03334-0.

Authors

Dae Hyun Song^{1

2

3}, Jong Sil Lee^{2

3

4}, Jeong-Hee Lee^{2

3

4}, Dong Chul Kim^{2

3

4}, Jung Wook Yang^{2

3

4}, Min Hye Kim⁴, Ji Min Na⁴, Hyun-Kyung Cho^{2

5}, Jiyun Yoo⁶, Hyo Jung An^{7

8

9}

Affiliations

¹ Department of Pathology, Gyeongsang National University Changwon Hospital, Changwon, South Korea.
² Institute of Medical Sciences, Gyeongsang National University, Jinju, South Korea.
³ Department of Pathology, Gyeongsang National University School of Medicine, Jinju, South Korea.
⁴ Department of Pathology, Gyeongsang National University Hospital, Jinju, South Korea.
⁵ Department of Ophthalmology, Gyeongsang National University Changwon Hospital, Gyeongsang National University, School of Medicine, Changwon, South Korea.
⁶ Division of Applied Life Science (BK21 Plus) and Research Institute of Life Sciences, Gyeongsang National University, Jinju, South Korea.
⁷ Department of Pathology, Gyeongsang National University Changwon Hospital, Changwon, South Korea. ariel2020@naver.com.
⁸ Institute of Medical Sciences, Gyeongsang National University, Jinju, South Korea. ariel2020@naver.com.
⁹ Department of Pathology, Gyeongsang National University School of Medicine, Jinju, South Korea. ariel2020@naver.com.

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.

Abstract

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