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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Oncol. | doi: 10.3389/fonc.2019.00447

The prognostic and therapeutic potential of LRIG3 and soluble LRIG3 in glioblastoma

 Fangling Cheng1, 2, Po Zhang1, 2,  Qungen Xiao1,  Youwei Li1, 2, Minhai Dong1, 2, Heping Wang1, Dong Kuang3, 4, Yue He1, Qiuhong Duan5, Feng Mao1, Baofeng Wang1* and  Dongsheng Guo1*
  • 1Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
  • 2Chinese-German Lab of Molecular Neuro-oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
  • 3Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
  • 4Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, China
  • 5Department of Biochemistry and Molecular Biology, School of Basic Medicine, Shanxi Medical University, China

Glioblastoma is a highly lethal type of primary brain tumor that exhibits unrestricted growth and aggressive invasion capabilities, leading to a dismal prognosis despite a multitude of therapies. Multiple alterations in the expression level of genes and/or proteins have been identified in glioblastomas, including the activation of oncogenes and/or silencing of tumor-suppressor genes. Nevertheless, there are still no effective targeted therapies associated with these changes. In this study, we investigated the expression of human leucine-rich repeats and immunoglobulin-like domains protein 3 (LRIG3) in human glioma specimens through immunohistochemical analysis. The results showed that LRIG3 was weakly expressed in high-grade gliomas (WHO [World Health Organization] grades Ⅲ and Ⅳ) compared with that in low-grade gliomas (WHO grade Ⅱ). Survival analysis of these patients with glioma indicated that LRIG3 is an important prognostic marker for better survival. Moreover, we confirmed the existence of soluble ectodomain of LRIG3 (sLRIG3) in the cell culture supernatant, serum, and in tumor cystic fluid of patients with glioma. Molecular mechanistic investigation demonstrated that both LRIG3 and sLRIG3 inhibit the growth and invasion capabilities of GL15, U87, and PriGBM cells and tumor xenografts in nude mice through regulating the MET/phosphatidylinositol 3-kinase/Akt signaling pathway. Enzyme-linked immunosorbent assay confirmed the positive correlation between serum sLRIG3 protein levels and overall survival time in patients with high-grade gliomas. Taken together, our data for the first time demonstrate the existence of sLRIG3 and that both LRIG3 and sLRIG3 are potent tumor suppressors, which could be used as prognostic markers for better overall survival and therapeutic agents for glioblastoma.

Keywords: Glioma, Glioblastoma, LRIG3, sLRIG3, MET/PI3K/Akt pathway, prognosis

Received: 14 Mar 2019; Accepted: 13 May 2019.

Edited by:

Thomas DAUBON, Institut National de la Santé et de la Recherche Médicale (INSERM), France

Reviewed by:

Justin Lathia, Cleveland Clinic Lerner College of Medicine, United States
Thomas Mathivet, INSERM U970 Paris-Centre de Recherche Cardiovasculaire (PARCC), France  

Copyright: © 2019 Cheng, Zhang, Xiao, Li, Dong, Wang, Kuang, He, Duan, Mao, Wang and Guo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. Baofeng Wang, Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China, wbf620@163.com
Prof. Dongsheng Guo, Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China, guodongsheng@yahoo.com