Abstract
BackgroundEmerging evidence has suggested that circulating microRNAs (miRNAs) in body fluids have novel diagnostic and prognostic significance for patients with malignant diseases. The lack of useful biomarkers is a crucial problem of bone and soft tissue sarcomas; therefore, we investigated the circulating miRNA signature and its clinical relevance in osteosarcoma.MethodsGlobal miRNA profiling was performed using patient serum collected from a discovery cohort of osteosarcoma patients and controls and cell culture media. The secretion of the detected miRNAs from osteosarcoma cells and clinical relevance of serum miRNA levels were evaluated using in vitro and in vivo models and a validation patient cohort.ResultsDiscovery screening identified 236 serum miRNAs that were highly expressed in osteosarcoma patients compared with controls, and eight among these were also identified in the cell culture media. Upregulated expression levels of miR-17-5p and miR-25-3p were identified in osteosarcoma cells, and these were abundantly secreted into the culture media in tumor-derived exosomes. Serum miR-25-3p levels were significantly higher in osteosarcoma patients than in control individuals in the validation cohort, with favorable sensitivity and specificity compared with serum alkaline phosphatase. Furthermore, serum miR-25-3p levels at diagnosis were correlated with patient prognosis and reflected tumor burden in both in vivo models and patients; these associations were more sensitive than those of serum alkaline phosphatase.ConclusionsSerum-based circulating miR-25-3p may serve as a non-invasive blood-based biomarker for tumor monitoring and prognostic prediction in osteosarcoma patients.
Highlights
The lack of useful biomarkers is one of the most important clinical problems of bone and soft tissue sarcomas
Discovery screening identified 236 serum miRNAs that were highly expressed in osteosarcoma patients compared with controls, and eight among these were identified in the cell culture media
Upregulated expression levels of miR-175p and miR-25-3p were identified in osteosarcoma cells, and these were abundantly secreted into the culture media in tumor-derived exosomes
Summary
The lack of useful biomarkers is one of the most important clinical problems of bone and soft tissue sarcomas. Along with the development of surgical techniques [3, 4] and multi-agent chemotherapy [5, 6], patient prognosis has gradually improved over the past 30 years. Development of methodologies for real-time monitoring of drug response and early detection of recurrence or metastasis will further improve patient prognosis. The development of highly sensitive, specific, and minimally invasive biomarkers that can be used to detect and monitor tumor burden of tumors is the most important challenge for osteosarcoma management. The lack of useful biomarkers is a crucial problem of bone and soft tissue sarcomas; we investigated the circulating miRNA signature and its clinical relevance in osteosarcoma
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