RAS‑stimulated release of exosomal <em>miR‑494‑3p</em> promotes the osteolytic bone metastasis of breast cancer cells

Kim,Okhwa; Kim,Okhwa; Tran,Phuong Thao; Tran,Phuong Thao; Gal,Minju; Gal,Minju; Lee,Se Jin; Lee,Se Jin; Na,Sung Hun; Na,Sung Hun; Hwangbo,Cheol; Hwangbo,Cheol; Lee,Jeong-Hyung; Lee,Jeong-Hyung

doi:10.3892/ijmm.2023.5287

RAS‑stimulated release of exosomal miR‑494‑3p promotes the osteolytic bone metastasis of breast cancer cells

Authors:
- Okhwa Kim
- Phuong Thao Tran
- Minju Gal
- Se Jin Lee
- Sung Hun Na
- Cheol Hwangbo
- Jeong-Hyung Lee
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Affiliations: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon‑Si, Gangwon‑Do 24341, Republic of Korea, Department of Obstetrics and Gynecology, Kangwon National University Hospital, School of Medicine, Kangwon National University, Chuncheon‑Si, Gangwon‑Do 24341, Republic of Korea, Division of Applied Life Science (BK21 Four), Division of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju, Gyeongsang 52828, Republic of Korea
Published online on: July 27, 2023 https://doi.org/10.3892/ijmm.2023.5287
Article Number: 84
Copyright: © Kim et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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.

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