Abstract
BackgroundMost patients with breast cancer in advanced stages of the disease suffer from bone metastases which lead to fractures and nerve compression syndromes. microRNA dysregulation is an important event in the metastases of breast cancer to bone. microRNA-124 (miR-124) has been proved to inhibit cancer progression, whereas its effect on bone metastases of breast cancer has not been reported. Therefore, this study aimed to investigate the role and underlying mechanism of miR-124 in bone metastases of breast cancer.MethodsIn situ hybridization (ISH) was used to detect the expression of miR-124 in breast cancer tissues and bone metastatic tissues. Ventricle injection model was constructed to explore the effect of miR-124 on bone metastasis in vivo. The function of cancer cell derived miR-124 in the differentiation of osteoclast progenitor cells was verified in vitro. Dual-luciferase reporter assay was conducted to confirm Interleukin-11 (IL-11) as a miR-124 target. The involvement of miR-124/IL-11 in the prognosis of breast cancer patients with bone metastasis was determined by Kaplan-Meier analysis.ResultsHerein, we found that miR-124 was significantly reduced in metastatic bone tissues from breast cancers. Down-regulation of miR-124 was associated with aggressive clinical characteristics and shorter bone metastasis-free survival and overall survival. Restoration of miR-124 suppressed, while inhibition of miR-124 promoted the bone metastasis of breast cancer cells in vivo. At the cellular level, gain of function and loss-of function assays indicated that cancer cell-derived miR-124 inhibited the survival and differentiation of osteoclast progenitor cells. At the molecular level, we demonstrated that IL-11 partially mediated osteoclastogenesis suppression by miR-124 using in vitro and in vivo assays. Furthermore, IL-11 levels were inversely correlated with miR-124, and up-regulation IL-11 in bone metastases was associated with a poor prognosis.ConclusionsThus, the identification of a dysregulated miR-124/IL-11 axis helps elucidate mechanisms of breast cancer metastases to bone, uncovers new prognostic markers, and facilitates the development of novel therapeutic targets to treat and even prevent bone metastases of breast cancer.
Highlights
Most patients with breast cancer in advanced stages of the disease suffer from bone metastases which lead to fractures and nerve compression syndromes. microRNA dysregulation is an important event in the metastases of breast cancer to bone. microRNA-124 has been proved to inhibit cancer progression, whereas its effect on bone metastases of breast cancer has not been reported
Results miR-124 is down-regulated in invasive breast cancer cells and human bone metastatic tissues We examined miR-124 expression in normal human mammary tissue and a panel of human breast cancer cell lines with different invasive properties. miR-124 levels were significantly decreased relative to the control in all of the eight tested breast cancer cell lines (Fig. 1a)
MDA-MB-231-luc-D3H2LN (MDA-MB-231-B) is a commonly used metastatic breast cancer cell line that has strong bone-metastatic characteristics. miR-124 expression was significantly down-regulated in MDA-MB-231-B compared to parental MDA-MB-231 cells (MDA-MB-231-P) (Fig. 1c)
Summary
Most patients with breast cancer in advanced stages of the disease suffer from bone metastases which lead to fractures and nerve compression syndromes. microRNA dysregulation is an important event in the metastases of breast cancer to bone. microRNA-124 (miR-124) has been proved to inhibit cancer progression, whereas its effect on bone metastases of breast cancer has not been reported. MicroRNA-124 (miR-124) has been proved to inhibit cancer progression, whereas its effect on bone metastases of breast cancer has not been reported. Cai et al Molecular Cancer (2018) 17:9 surviving in the bone microenvironment [5] In this microenvironment, tumor cells have complicated interactions with osteoblasts, osteoclasts and bone stromal cells, which leads to osteogenesis/osteoclastogenesis imbalance, enabling breast cancer cells to form osteolytic lesions in bone and causing SREs [6]. Tumor cells have complicated interactions with osteoblasts, osteoclasts and bone stromal cells, which leads to osteogenesis/osteoclastogenesis imbalance, enabling breast cancer cells to form osteolytic lesions in bone and causing SREs [6] This process is controlled by systemic and local signals as well as a number of cytokines, such as IL-11 [7]. IL-11 inhibitors involved in breast tumor-stromal interactions have been poorly defined
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
