title: Extracellular miRNA-21 as a novel biomarker in glioma: Evidence from meta-analysis, clinical validation and experimental investigations.
abstract: Evidence is accumulating highlighting the importance of extracellular miRNA as a novel biomarker for diagnosing various kinds of malignancies. MiR-21 is one of the most studied miRNAs and is over-expressed in cancer tissues. To explore the clinical implications and secretory mechanisms of extracellular miR-21, we firstly meta-analyzed the diagnostic efficiency of extracellular miR-21 in different cancer types. Eighty-one studies based on 59 articles were finally included. In our study, extracellular miR-21 was observed to exhibit an outstanding diagnostic accuracy in detecting brain cancer (area under the summary receiver operating characteristic curve or AUC = 0.94), and this accuracy was more obvious in glioma diagnosis (AUC = 0.95). Our validation study (n = 45) further confirmed the diagnostic and prognostic role of miR-21 in cerebrospinal fluid (CSF) for glioma. These findings inspired us to explore the biological function of miR-21. We next conducted mechanistic investigations to explain the secretory mechanisms of extracellular miR-21 in glioma. TGF-β/Smad3 signaling was identified to participate in mediating the release of miR-21 from glioma cells. Further targeting TGF-β/Smad3 signaling using galunisertib, an inhibitor of the TGF-β type I receptor kinase, can attenuate the secretion of miR-21 from glioma cells. Taken together, CSF-based miR-21 might serve as a potential biomarker for diagnosing brain cancer, especially for patients with glioma. Moreover, extracellular levels of miR-21 were affected by exogenous TGF-β activity and galunisertib treatment.
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Qu
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Lin
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Pang
authors.affiliation: Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, Shaanxi, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Hepatobiliary Surgery, The Affiliated Hospital of Qinghai University, Xining 810001, Qinghai, China.|Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Ultrasound Diagnostics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.|Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Minghui
authors.initials: M
authors.lastname: Tai
authors.affiliation: Department of Geriatric Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Fandi
authors.initials: F
authors.lastname: Meng
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Jingyao
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Geriatric Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Mao
authors.affiliation: Department of Internal Medicine, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
authors.forename: Wenquan
authors.initials: W
authors.lastname: Niu
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
authors.forename: Shunbin
authors.initials: S
authors.lastname: Dong
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000378:metabolism; D001932:Brain Neoplasms / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D005910:Glioma / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000134:cerebrospinal fluid / Q000235:genetics*; D025202:Molecular Diagnostic Techniques; D011237:Predictive Value of Tests; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D034741:RNA, Small Interfering; D012372:ROC Curve; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D011720:Pyrazoles; D011804:Quinolines; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; C497790:SMAD3 protein, human; D051900:Smad3 Protein; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; C557799:LY-2157299; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I
keywords: TGF-β/Smad3 signaling; cerebrospinal fluid; diagnosis; extracellular miR-21; glioma