RASstimulated release of exosomal miR4943p promotes the osteolytic bone metastasis of breast cancer cells.
Int J Mol Med
; 52(3)2023 09.
Article
em En
| MEDLINE
| ID: mdl-37503759
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 exosomemediated osteoclastogenic miRNAs and to elucidate their functional role in bone microenvironment remodeling in vitro and in vivo. Exosomes derived from RASactivated breast cancer cells promoted RANKLinduced osteoclastogenesis; however, RAS inhibition abolished this effect. miR4943p, miR4508 and miR68695p were identified as osteoclastogenic miRNAs in the exosomes secreted by RASactivated breast cancer cells. The levels of these osteoclastogenic miRNAs in the sera of patients with human epidermal growth factor receptor 2positive luminal breast cancer were significantly higher than those in the sera of patients with triplenegative breast cancer. miR4943p exhibited both osteoclastogenic and antiosteoblastogenic activity. Treatment with a miR4943p inhibitor abolished the exosomemediated increase in RANKLinduced osteoclastogenesis. Treatment with a miR4943p mimic enhanced RANKLinduced osteoclast formation; however, treatment with its inhibitor suppressed this effect by targeting leucinerich repeatcontaining Gprotein coupled receptor 4 in osteoclast precursors. Furthermore, miR4943p inhibited bone morphogenetic protein 2induced osteoblast formation by targeting semaphorin 3A. In a mouse model, exosomes derived from breast cancer cells promoted osteolytic bone lesions; however, treatment with a miR4943p 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 exosomemediated transfer of osteoclastogenic miRNAs, including miR4943p to bone cells.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Ósseas
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Neoplasias da Mama
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MicroRNAs
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Neoplasias de Mama Triplo Negativas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Int J Mol Med
Assunto da revista:
BIOLOGIA MOLECULAR
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GENETICA MEDICA
Ano de publicação:
2023
Tipo de documento:
Article