Clinical significance of circulating miR-25-3p as a novel diagnostic and prognostic biomarker in osteosarcoma
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Tomohiro Fujiwara1,2,3, Koji Uotani1, Aki Yoshida1, Takuya Morita1, Yutaka Nezu3, Eisuke Kobayashi4, Akihiko Yoshida5, Takenori Uehara1, Toshinori Omori1, Kazuhisa Sugiu1, Tadashi Komatsubara1, Ken Takeda6, Toshiyuki Kunisada7, Machiko Kawamura8, Akira Kawai4, Takahiro Ochiya3, Toshifumi Ozaki1
1Department of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
2Center of Innovative Medicine, Okayama University Hospital, Okayama, Japan
3Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
4Department of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan
5Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
6Department of Intelligent Orthopaedic System, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
7Department of Medical Materials for Musculoskeletal Reconstruction, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
8Department of Hematology, Saitama Cancer Center, Saitama, Japan
Tomohiro Fujiwara, email: firstname.lastname@example.org
Keywords: microRNA, liquid biopsy, osteosarcoma, biomarker, prognosis
Received: September 24, 2016 Accepted: February 27, 2017 Published: March 23, 2017
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.
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