Abstract
e14534 Background: 20-40% of lung cancer patients develop bone metastasis (BM) with significantly decreased overall survival. Currently, BM is mainly diagnosed by CT scan or MRI when symptom develop. Novel biomarkers with higher prediction value of BM are needed. Tumor secreted exosomes that are enriched with microRNAs have been recently implicated in site-specific tumor metastasis for establishing a distant pro-metastatic niche. Methods: Plasma exosomes from 39 stage IV non-small cell lung cancer (NSCLC) patients (n = 23 with BM; n = 16 without BM) and 16 healthy individuals were separated by ultracentrifugation. Total RNAs were extracted followed by small RNA-sequencing. miRNA identification was performed by miRDeep2. Weighted correlation network analysis (WGCNA) was used for identifying co-expression networks of highly correlated miRNA clusters. miRNA enrichment analysis and annotation (MIEAA) was applied for pathway analysis. Differential expression of individual miRNA was analyzed by edgeR. Results: Hierarchical clustering based on the total miRNA profile can clearly separate cancer patients and healthy individuals (HP), but not patients with (BM+) or without (BM-) BM. WGCNA identified three consensus clusters (A, B, C) of highly correlated miRNAs, among which cluster A (144 miRNAs) showed significantly differential expression in lung cancer patients, especially in BM+ group. Pathway analysis of cluster B miRNAs revealed enrichment in glycolysis and gluconeogenesis pathways that may involve in metabolic preconditioning of the metastatic niche. Three differentially expressed miRNAs between BM+ and BM- patients within cluster A were identified as miR-574-5p, a suppressor of Wnt/β-catenin pathway, was down-regulated, while miR-328-3p and miR-423-3p, two activators of the same pathway, were up-regulated in BM+ patients. Cluster B miRNAs (n = 49) also showed trend of upregulation in BM+ patients. Interestingly, pathway analysis indicated that 43 of them are associated with chr14, which has been suggested to promote EMT and bone metastasis. Conclusions: NSCLC patients with BM displayed unique plasma exosomal miRNA profiles, which might involve in promoting BM, and be potential biomarkers for predicting BM in NSCLC.
Highlights
Pathway analysis indicated that 43 of them are associated with chromosome14, which has been suggested to promote epithelial-mesenchymal transition (EMT) and bone metastasis
Lung cancer is the leading cause of cancer death worldwide and non-small cell lung cancer (NSCLC) which account for 80% of lung cancers[1] is one of the most common tumors metastasizing to bone
Invasive tumor cells may intrude into the blood vessel as single circulating tumor cells (CTCs) which is facilitated by epithelial-mesenchymal transition (EMT) and the primary tumor microenvironment
Summary
Prospective analysis was undertaken on non-small cell lung cancer (NSCLC) patients with (BM+) and without BM (BM-). Plasma exosomal RNA was isolated and sequenced from peripheral blood of patients. Differential expression analysis and weighted gene co-expression networks analysis (WGCNA) of mi-RNA sequencing data were performed between two groups
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