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// Tomohiro Fujiwara 1, 2, 3 , Koji Uotani 1 , Aki Yoshida 1 , Takuya Morita 1 , Yutaka Nezu 3 , Eisuke Kobayashi 4 , Akihiko Yoshida 5 , Takenori Uehara 1 , Toshinori Omori 1 , Kazuhisa Sugiu 1 , Tadashi Komatsubara 1 , Ken Takeda 6 , Toshiyuki Kunisada 7 , Machiko Kawamura 8 , Akira Kawai 4 , Takahiro Ochiya 3 , Toshifumi Ozaki 1 1 Department of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan 2 Center of Innovative Medicine, Okayama University Hospital, Okayama, Japan 3 Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan 4 Department of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan 5 Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan 6 Department of Intelligent Orthopaedic System, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan 7 Department of Medical Materials for Musculoskeletal Reconstruction, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan 8 Department of Hematology, Saitama Cancer Center, Saitama, Japan Correspondence to: Tomohiro Fujiwara, email: tomomedvn@gmail.com Keywords: microRNA, liquid biopsy, osteosarcoma, biomarker, prognosis Received: September 24, 2016 Accepted: February 27, 2017 Published: March 23, 2017 ABSTRACT Background: Emerging 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. Methods: Global 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. Results: Discovery 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. Conclusions: Serum-based circulating miR-25-3p may serve as a non-invasive blood-based biomarker for tumor monitoring and prognostic prediction in osteosarcoma patients. |
