Abstract
Bone is a frequent metastatic site of non-small cell lung cancer (NSCLC), and bone metastasis (BoM) presents significant challenges for patient survival and quality of life. Osteolytic BoM is characterised by aberrant differentiation and malfunction of osteoclasts through modulation of the TGF-β/pTHrP/RANKL signalling pathway, but its upstream regulatory mechanism is unclear. In this study, we found that lncRNA-SOX2OT was highly accumulated in exosomes derived from the peripheral blood of NSCLC patients with BoM and that patients with higher expression of exosomal lncRNA-SOX2OT had significantly shorter overall survival. Additionally, exosomal lncRNA-SOX2OT derived from NSCLC cells promoted cell invasion and migration in vitro, as well as BoM in vivo. Mechanistically, we discovered that NSCLC cell-derived exosomal lncRNA-SOX2OT modulated osteoclast differentiation and stimulated BoM by targeting the miRNA-194-5p/RAC1 signalling axis and TGF-β/pTHrP/RANKL signalling pathway in osteoclasts. In conclusion, exosomal lncRNA-SOX2OT plays a crucial role in promoting BoM and may serve as a promising prognostic biomarker and treatment target in metastatic NSCLC.
Highlights
Bone metastasis (BoM) is one of the important factors leading to increased rates of disease recurrence and mortality in cancer patients, and it occurs frequently in lung cancer, breast cancer and prostate cancer [1]
Our data will show the clinical significance that exosomal lncRNA-SOX2OT may serve as a powerful prognostic biomarker for non-small cell lung cancer (NSCLC) patients with BoM and uncover a molecular mechanism by which NSCLC cell-derived exosomal lncRNASOX2OT modulates osteoclast differentiation and stimulates BoM by targeting the miRNA-194-5p/RAC1 signalling axis and transforming growth factor-β (TGF-β)/ parathyroid hormone related protein (pTHrP)/RANK ligand (RANKL) signalling pathway in osteoclasts
Exosomal lncRNA-SOX2OT expression is upregulated in NSCLC patients with BoM and correlates with shortened survival Exosomes were extracted from the plasma of NSCLC patients with or without BoM
Summary
Bone metastasis (BoM) is one of the important factors leading to increased rates of disease recurrence and mortality in cancer patients, and it occurs frequently in lung cancer, breast cancer and prostate cancer [1]. The vast majority of NSCLC BoM lesions are osteolytic, which manifest as bone tissue dissolution, destruction and resorption. Tumour cells can stimulate the activation of osteoclasts, which are the key mediators of the bone resorption process [5]. NSCLC cells can stimulate the receptor activator of NF-κB (RANK) pathway in osteoblasts by altering the microenvironment of the bone tissue, allowing the body to misjudge the bone balance. The naturally secreted decoy receptor osteoprotegerin (OPG) inhibits osteoclast maturation and activation, inducing osteoclast apoptosis and inhibiting bone resorption [7, 8]
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