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RAS-stimulated release of exosomal miR-494-3p promotes the osteolytic bone metastasis of breast cancer cells
RAS activation is a key determinant of breast cancer progression and metastasis. However, the role of the interaction among exosomes, RAS and microRNAs (miRNAs/miRs) in the osteolytic bone metastasis of breast cancer remains unclear. Therefore, the present study aimed to examine the role of activate...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
D.A. Spandidos
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10555479/ https://www.ncbi.nlm.nih.gov/pubmed/37503759 http://dx.doi.org/10.3892/ijmm.2023.5287 |
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author | Kim, Okhwa Tran, Phuong Thao Gal, Minju Lee, Se Jin Na, Sung Hun Hwangbo, Cheol Lee, Jeong-Hyung |
author_facet | Kim, Okhwa Tran, Phuong Thao Gal, Minju Lee, Se Jin Na, Sung Hun Hwangbo, Cheol Lee, Jeong-Hyung |
author_sort | Kim, Okhwa |
collection | PubMed |
description | RAS activation is a key determinant of breast cancer progression and metastasis. However, the role of the interaction among exosomes, RAS and microRNAs (miRNAs/miRs) in the osteolytic bone metastasis of breast cancer remains unclear. Therefore, the present study aimed to examine the role of activated RAS (KRAS, HRAS and NRAS) in the release of exosome-mediated osteoclastogenic miRNAs and to elucidate their functional role in bone microenvironment remodeling in vitro and in vivo. Exosomes derived from RAS-activated breast cancer cells promoted RANKL-induced osteoclastogenesis; however, RAS inhibition abolished this effect. miR-494-3p, miR-4508 and miR-6869-5p were identified as osteoclastogenic miRNAs in the exosomes secreted by RAS-activated breast cancer cells. The levels of these osteoclastogenic miRNAs in the sera of patients with human epidermal growth factor receptor 2-positive luminal breast cancer were significantly higher than those in the sera of patients with triple-negative breast cancer. miR-494-3p exhibited both osteoclastogenic and anti-osteoblastogenic activity. Treatment with a miR-494-3p inhibitor abolished the exosome-mediated increase in RANKL-induced osteoclastogenesis. Treatment with a miR-494-3p mimic enhanced RANKL-induced osteoclast formation; however, treatment with its inhibitor suppressed this effect by targeting leucine-rich repeat-containing G-protein coupled receptor 4 in osteoclast precursors. Furthermore, miR-494-3p inhibited bone morphogenetic protein 2-induced osteoblast formation by targeting semaphorin 3A. In a mouse model, exosomes derived from breast cancer cells promoted osteolytic bone lesions; however, treatment with a miR-494-3p inhibitor significantly suppressed this effect. On the whole, the present study provides a novel mechanism, demonstrating that the RAS activation of breast cancer cells induces osteolytic bone metastasis by stimulating the exosome-mediated transfer of osteoclastogenic miRNAs, including miR-494-3p to bone cells. |
format | Online Article Text |
id | pubmed-10555479 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | D.A. Spandidos |
record_format | MEDLINE/PubMed |
spelling | pubmed-105554792023-10-06 RAS-stimulated release of exosomal miR-494-3p promotes the osteolytic bone metastasis of breast cancer cells Kim, Okhwa Tran, Phuong Thao Gal, Minju Lee, Se Jin Na, Sung Hun Hwangbo, Cheol Lee, Jeong-Hyung Int J Mol Med Articles RAS activation is a key determinant of breast cancer progression and metastasis. However, the role of the interaction among exosomes, RAS and microRNAs (miRNAs/miRs) in the osteolytic bone metastasis of breast cancer remains unclear. Therefore, the present study aimed to examine the role of activated RAS (KRAS, HRAS and NRAS) in the release of exosome-mediated osteoclastogenic miRNAs and to elucidate their functional role in bone microenvironment remodeling in vitro and in vivo. Exosomes derived from RAS-activated breast cancer cells promoted RANKL-induced osteoclastogenesis; however, RAS inhibition abolished this effect. miR-494-3p, miR-4508 and miR-6869-5p were identified as osteoclastogenic miRNAs in the exosomes secreted by RAS-activated breast cancer cells. The levels of these osteoclastogenic miRNAs in the sera of patients with human epidermal growth factor receptor 2-positive luminal breast cancer were significantly higher than those in the sera of patients with triple-negative breast cancer. miR-494-3p exhibited both osteoclastogenic and anti-osteoblastogenic activity. Treatment with a miR-494-3p inhibitor abolished the exosome-mediated increase in RANKL-induced osteoclastogenesis. Treatment with a miR-494-3p mimic enhanced RANKL-induced osteoclast formation; however, treatment with its inhibitor suppressed this effect by targeting leucine-rich repeat-containing G-protein coupled receptor 4 in osteoclast precursors. Furthermore, miR-494-3p inhibited bone morphogenetic protein 2-induced osteoblast formation by targeting semaphorin 3A. In a mouse model, exosomes derived from breast cancer cells promoted osteolytic bone lesions; however, treatment with a miR-494-3p inhibitor significantly suppressed this effect. On the whole, the present study provides a novel mechanism, demonstrating that the RAS activation of breast cancer cells induces osteolytic bone metastasis by stimulating the exosome-mediated transfer of osteoclastogenic miRNAs, including miR-494-3p to bone cells. D.A. Spandidos 2023-07-27 /pmc/articles/PMC10555479/ /pubmed/37503759 http://dx.doi.org/10.3892/ijmm.2023.5287 Text en Copyright: © Kim et al. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
spellingShingle | Articles Kim, Okhwa Tran, Phuong Thao Gal, Minju Lee, Se Jin Na, Sung Hun Hwangbo, Cheol Lee, Jeong-Hyung RAS-stimulated release of exosomal miR-494-3p promotes the osteolytic bone metastasis of breast cancer cells |
title | RAS-stimulated release of exosomal miR-494-3p promotes the osteolytic bone metastasis of breast cancer cells |
title_full | RAS-stimulated release of exosomal miR-494-3p promotes the osteolytic bone metastasis of breast cancer cells |
title_fullStr | RAS-stimulated release of exosomal miR-494-3p promotes the osteolytic bone metastasis of breast cancer cells |
title_full_unstemmed | RAS-stimulated release of exosomal miR-494-3p promotes the osteolytic bone metastasis of breast cancer cells |
title_short | RAS-stimulated release of exosomal miR-494-3p promotes the osteolytic bone metastasis of breast cancer cells |
title_sort | ras-stimulated release of exosomal mir-494-3p promotes the osteolytic bone metastasis of breast cancer cells |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10555479/ https://www.ncbi.nlm.nih.gov/pubmed/37503759 http://dx.doi.org/10.3892/ijmm.2023.5287 |
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