title: γ-Glutamyl transferase 7 is a novel regulator of glioblastoma growth.
abstract: BACKGROUND
  Glioblastoma (GBM) is the most malignant primary brain tumor in adults, with a median survival time of one and a half years. Traditional treatments, including radiation, chemotherapy, and surgery, are not curative, making it imperative to find more effective treatments for this lethal disease. γ-Glutamyl transferase (GGT) is a family of enzymes that was shown to control crucial redox-sensitive functions and to regulate the balance between proliferation and apoptosis. GGT7 is a novel GGT family member that is highly expressed in brain and was previously shown to have decreased expression in gliomas. Since other members of the GGT family were found to be altered in a variety of cancers, we hypothesized that GGT7 could regulate GBM growth and formation.
  
  
  METHODS
  To determine if GGT7 is involved in GBM tumorigenesis, we modulated GGT7 expression in two GBM cell lines (U87-MG and U138) and monitored changes in tumorigenicity in vitro and in vivo.
  
  
  RESULTS
  We demonstrated for the first time that GBM patients with low GGT7 expression had a worse prognosis and that 87% (7/8) of primary GBM tissue samples showed a 2-fold decrease in GGT7 expression compared to normal brain samples. Exogenous expression of GGT7 resulted in a 2- to 3-fold reduction in proliferation and anchorage-independent growth under minimal growth conditions (1% serum). Decreasing GGT7 expression using either short interfering RNA or short hairpin RNA consistently increased proliferation 1.5- to 2-fold. In addition, intracranial injections of U87-MG cells with reduced GGT7 expression increased tumor growth in mice approximately 2-fold, and decreased mouse survival. To elucidate the mechanism by which GGT7 regulates GBM growth, we analyzed reactive oxygen species (ROS) levels in GBM cells with modulated GGT7 expression. We found that enhanced GGT7 expression reduced ROS levels by 11-33%.
  
  
  CONCLUSIONS
  Our study demonstrates that GGT7 is a novel player in GBM growth and that GGT7 can play a critical role in tumorigenesis by regulating anti-oxidative damage. Loss of GGT7 may increase the cellular ROS levels, inducing GBM occurrence and growth. Our findings suggest that GGT7 can be a promising biomarker and a potential therapeutic target for GBM.
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Institute for Stem Cell Biology and Regenerative Medicine, 1201 Welch Rd P309, Stanford, CA, 94305-5487, USA. timbui@stanford.edu.
authors.forename: Timothy T
authors.initials: TT
authors.lastname: Bui
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Institute for Stem Cell Biology and Regenerative Medicine, 1201 Welch Rd P309, Stanford, CA, 94305-5487, USA. rnitta@stanford.edu.
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Nitta
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Institute for Stem Cell Biology and Regenerative Medicine, 1201 Welch Rd P309, Stanford, CA, 94305-5487, USA. suzanakahn@gmail.com.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. suzanakahn@gmail.com.
authors.forename: Suzana A
authors.initials: SA
authors.lastname: Kahn
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Institute for Stem Cell Biology and Regenerative Medicine, 1201 Welch Rd P309, Stanford, CA, 94305-5487, USA. mostafa_razavi@yahoo.com.
authors.forename: Seyed-Mostafa
authors.initials: SM
authors.lastname: Razavi
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Institute for Stem Cell Biology and Regenerative Medicine, 1201 Welch Rd P309, Stanford, CA, 94305-5487, USA. maya.agarwal26@gmail.com.
authors.forename: Maya
authors.initials: M
authors.lastname: Agarwal
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Institute for Stem Cell Biology and Regenerative Medicine, 1201 Welch Rd P309, Stanford, CA, 94305-5487, USA. aujla.parvir@gmail.com.
authors.forename: Parvir
authors.initials: P
authors.lastname: Aujla
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Institute for Stem Cell Biology and Regenerative Medicine, 1201 Welch Rd P309, Stanford, CA, 94305-5487, USA. sharar@stanford.edu.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. sharar@stanford.edu.
authors.forename: Sharareh
authors.initials: S
authors.lastname: Gholamin
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA. LRecht@stanford.edu.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Recht
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Institute for Stem Cell Biology and Regenerative Medicine, 1201 Welch Rd P309, Stanford, CA, 94305-5487, USA. gordonli@stanford.edu.
authors.forename: Gordon
authors.initials: G
authors.lastname: Li
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D064593:Heterografts; D006801:Humans; D011379:Prognosis; D017382:Reactive Oxygen Species / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000235:genetics / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D005723:gamma-Glutamyltransferase