Extracellular miRNA-21 as a novel biomarker in glioma: evidence from meta-analysis, clinical validation and experimental investigations
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Kai Qu1,*, Ting Lin1,*, Qing Pang1,*, Tian Liu2, Zhixin Wang3,1, Minghui Tai4,1, Fandi Meng5, Jingyao Zhang1, Yong Wan5, Ping Mao6, Xiaoqun Dong7, Chang Liu1, Wenquan Niu8, Shunbin Dong1
1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi, China
2Department of Hematology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi, China
3Department of Hepatobiliary Surgery, The Affiliated Hospital of Qinghai University, Xining 810001, Qinghai, China
4Department of Ultrasound Diagnostics, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi, China
5Department of Geriatric Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi, China
6Department of Neurosurgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi, China
7Department of Internal Medicine, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA
8State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
*These authors contributed equally to this work
Shunbin Dong, email: [email protected]
Chang Liu, email: [email protected]
Wenquan Niu, email: [email protected]
Keywords: extracellular miR-21, cerebrospinal fluid, glioma, diagnosis, TGF-β/Smad3 signaling
Received: February 24, 2016 Accepted: April 16, 2016 Published: May 05, 2016
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.
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