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

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.

Role of Semaphorin 3A in Kidney Development and Diseases

“…Since then, SEMA3A has been well studied not only in axon guidance, but also in pleiotropic functions, including in angiogenesis, immune cell regulation and cell migration [6]. SEMA3A is expressed in kidneys, as well as the nervous system, heart, lung, eyes, bone and immune cells [7][8][9][10][11][12], and regulates tissue development and the maintenance of homeostasis, for example, through the regulation of cell proliferation and migration, and the immune system [13][14][15]. Several reports have identified an increase or decrease in SEMA3A expression under several disease conditions [16][17][18][19]; thus, SEMA3A has been suggested as a possible biomarker, as well as a therapeutic target.…”

The Emerging Roles of Exosomal miRNAs in Breast Cancer Progression and Potential Clinical Applications

“…16 In addition, Kim et al showed that RAS activation in BC cells triggered osteolytic bone metastasis by exciting exosome-mediated osteoclast production of miRNAs, including miR-494-3p, to osteoblasts. 17 This feature makes exosomal miRNAs derived from tumor tissue or other body fluids high-value indicators for tumor differential diagnosis, treatment monitoring, and prognosis evaluation. 18 Given the increasingly prominent roles of exosomal miRNAs in BC, here we highlight the novel roles and mechanisms of exosomal miRNAs, including BC progression regulation, as well as their roles in clinical BC diagnosis and treatment.…”