title: Clinical significance of circulating miR-25-3p as a novel diagnostic and prognostic biomarker in osteosarcoma.
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.
authors.affiliation: Department of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.|Center of Innovative Medicine, Okayama University Hospital, Okayama, Japan.|Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Fujiwara
authors.affiliation: Department of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Uotani
authors.affiliation: Department of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Yoshida
authors.affiliation: Department of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Morita
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nezu
authors.affiliation: Department of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Eisuke
authors.initials: E
authors.lastname: Kobayashi
authors.affiliation: Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshida
authors.affiliation: Department of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Takenori
authors.initials: T
authors.lastname: Uehara
authors.affiliation: Department of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Omori
authors.affiliation: Department of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Sugiu
authors.affiliation: Department of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Komatsubara
authors.affiliation: Department of Intelligent Orthopaedic System, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Department of Medical Materials for Musculoskeletal Reconstruction, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kunisada
authors.affiliation: Department of Hematology, Saitama Cancer Center, Saitama, Japan.
authors.forename: Machiko
authors.initials: M
authors.lastname: Kawamura
authors.affiliation: Department of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kawai
authors.affiliation: Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ochiya
authors.affiliation: Department of Orthopedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Ozaki
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D014408:Biomarkers, Tumor; D001773:Blood Cells / Q000378:metabolism; D001859:Bone Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D000074166:Circulating MicroRNA; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D055354:Exosomes; D005260:Female; D020869:Gene Expression Profiling; D064593:Heterografts; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D000073890:Liquid Biopsy; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D012516:Osteosarcoma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D011379:Prognosis; D012372:ROC Curve; D015203:Reproducibility of Results; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D000074166:Circulating MicroRNA; C524941:MIRN17 microRNA, human; C543351:MIRN25 microRNA, human; D035683:MicroRNAs
keywords: biomarker; liquid biopsy; microRNA; osteosarcoma; prognosis