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.
Int J Mol Med. 2023 Sep;52(3). doi: 10.3892/ijmm.2023.5287. Epub 2023 Jul 28.
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 and . Exosomes derived from RAS‑activated breast cancer cells promoted RANKL‑induced osteoclastogenesis; however, RAS inhibition abolished this effect. and 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. exhibited both osteoclastogenic and anti‑osteoblastogenic activity. Treatment with a inhibitor abolished the exosome‑mediated increase in RANKL‑induced osteoclastogenesis. Treatment with a 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, 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 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 to bone cells.
RAS 激活是乳腺癌进展和转移的关键决定因素。然而，外泌体、RAS 和 microRNAs（miRNAs/miRs）之间的相互作用在乳腺癌溶骨性骨转移中的作用尚不清楚。因此，本研究旨在研究激活的 RAS（KRAS、HRAS 和 NRAS）在释放外泌体介导的破骨细胞生成 miRNA 中的作用，并阐明它们在骨微环境重塑中的功能作用。RAS 激活的乳腺癌细胞来源的外泌体促进了 RANKL 诱导的破骨细胞生成；然而，RAS 抑制消除了这种作用。 和 被鉴定为 RAS 激活的乳腺癌细胞分泌的外泌体中的破骨细胞生成 miRNA。人表皮生长因子受体 2 阳性腔乳腺癌患者血清中这些破骨细胞生成 miRNA 的水平明显高于三阴性乳腺癌患者血清中的水平。表现出破骨细胞生成和抗成骨细胞生成活性。用 抑制剂处理可消除外泌体介导的 RANKL 诱导的破骨细胞生成增加。用 模拟物处理增强了 RANKL 诱导的破骨细胞形成；然而，用其抑制剂处理通过靶向破骨细胞前体中的富含亮氨酸重复的 G 蛋白偶联受体 4 抑制了这种作用。此外， 通过靶向 SEMA3A 抑制骨形态发生蛋白 2 诱导的成骨细胞形成。在小鼠模型中，乳腺癌细胞来源的外泌体促进溶骨性骨病变；然而，用 抑制剂处理可显著抑制这种作用。总的来说，本研究提供了一种新的机制，表明乳腺癌细胞的 RAS 激活通过刺激包括 在内的破骨细胞生成 miRNA 向骨细胞的外泌体介导转移，诱导溶骨性骨转移。
