title: Human cytomegalovirus may promote tumour progression by upregulating arginase-2.
abstract: BACKGROUND
  Both arginase (ARG2) and human cytomegalovirus (HCMV) have been implicated in tumorigenesis. However, the role of ARG2 in the pathogenesis of glioblastoma (GBM) and the HCMV effects on ARG2 are unknown. We hypothesize that HCMV may contribute to tumorigenesis by increasing ARG2 expression.
  
  
  RESULTS
  ARG2 promotes tumorigenesis by increasing cellular proliferation, migration, invasion and vasculogenic mimicry in GBM cells, at least in part due to overexpression of MMP2/9. The nor-NOHA significantly reduced migration and tube formation of ARG2-overexpressing cells. HCMV immediate-early proteins (IE1/2) or its downstream pathways upregulated the expression of ARG2 in U-251 MG cells. Immunostaining of GBM tissue sections confirmed the overexpression of ARG2, consistent with data from subsets of Gene Expression Omnibus. Moreover, higher levels of ARG2 expression tended to be associated with poorer survival in GBM patient by analyzing data from TCGA.
  
  
  METHODS
  The role of ARG2 in tumorigenesis was examined by proliferation-, migration-, invasion-, wound healing- and tube formation assays using an ARG2-overexpressing cell line and ARG inhibitor, N (omega)-hydroxy-nor-L-arginine (nor-NOHA) and siRNA against ARG2 coupled with functional assays measuring MMP2/9 activity, VEGF levels and nitric oxide synthase activity. Association between HCMV and ARG2 were examined in vitro with 3 different GBM cell lines, and ex vivo with immunostaining on GBM tissue sections. The viral mechanism mediating ARG2 induction was examined by siRNA approach. Correlation between ARG2 expression and patient survival was extrapolated from bioinformatics analysis on data from The Cancer Genome Atlas (TCGA).
  
  
  CONCLUSIONS
  ARG2 promotes tumorigenesis, and HCMV may contribute to GBM pathogenesis by upregulating ARG2.
authors.affiliation: Cell and Molecular Immunology, Department of Medicine, Center for Molecular Medicine, Unit for Experimental Cardiovascular Research and Department of Neurology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Costa
authors.affiliation: Cell and Molecular Immunology, Department of Medicine, Center for Molecular Medicine, Unit for Experimental Cardiovascular Research and Department of Neurology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Xinling
authors.initials: X
authors.lastname: Xu
authors.affiliation: Cell and Molecular Immunology, Department of Medicine, Center for Molecular Medicine, Unit for Experimental Cardiovascular Research and Department of Neurology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Gitta
authors.initials: G
authors.lastname: Overbeek
authors.affiliation: Unit of Computational Medicine, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Suhas
authors.initials: S
authors.lastname: Vasaikar
authors.affiliation: Social & Cognitive Computing Department, Institute of High Performance Computing, Agency for Science, Technology and Research, Singapore.
authors.forename: C Pawan K
authors.initials: CP
authors.lastname: Patro
authors.affiliation: Cell and Molecular Immunology, Department of Medicine, Center for Molecular Medicine, Unit for Experimental Cardiovascular Research and Department of Neurology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ourania N
authors.initials: ON
authors.lastname: Kostopoulou
authors.affiliation: Cell and Molecular Immunology, Department of Medicine, Center for Molecular Medicine, Unit for Experimental Cardiovascular Research and Department of Neurology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Masany
authors.initials: M
authors.lastname: Jung
authors.affiliation: Department of Genomics and Bioinformatics, Positive Bioscience, Mumbai, India.
authors.forename: Gowhar
authors.initials: G
authors.lastname: Shafi
authors.affiliation: Cell and Molecular Immunology, Department of Medicine, Center for Molecular Medicine, Unit for Experimental Cardiovascular Research and Department of Neurology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sharan
authors.initials: S
authors.lastname: Ananthaseshan
authors.affiliation: Unit of Computational Medicine, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Giorgos
authors.initials: G
authors.lastname: Tsipras
authors.affiliation: Cell and Molecular Immunology, Department of Medicine, Center for Molecular Medicine, Unit for Experimental Cardiovascular Research and Department of Neurology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Belghis
authors.initials: B
authors.lastname: Davoudi
authors.affiliation: Cell and Molecular Immunology, Department of Medicine, Center for Molecular Medicine, Unit for Experimental Cardiovascular Research and Department of Neurology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Abdul-Aleem
authors.initials: AA
authors.lastname: Mohammad
authors.affiliation: Cell and Molecular Immunology, Department of Medicine, Center for Molecular Medicine, Unit for Experimental Cardiovascular Research and Department of Neurology, Karolinska Institutet, Stockholm, Sweden.|Present affiliation: Division of Cancer Studies, King's College London, London, UK.
authors.forename: Hoyin
authors.initials: H
authors.lastname: Lam
authors.affiliation: Cell and Molecular Immunology, Department of Medicine, Center for Molecular Medicine, Unit for Experimental Cardiovascular Research and Department of Neurology, Karolinska Institutet, Stockholm, Sweden.|Division of Gene Technology, School of Biotechnology, Science for Life Laboratory, Royal Institute of Technology (KTH), Solna, Sweden.
authors.forename: Klas
authors.initials: K
authors.lastname: Strååt
authors.affiliation: Cell and Molecular Immunology, Department of Medicine, Center for Molecular Medicine, Unit for Experimental Cardiovascular Research and Department of Neurology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Wilhelmi
authors.affiliation: Unit of Computational Medicine, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mingmei
authors.initials: M
authors.lastname: Shang
authors.affiliation: Unit of Computational Medicine, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jesper
authors.initials: J
authors.lastname: Tegner
authors.affiliation: Social & Cognitive Computing Department, Institute of High Performance Computing, Agency for Science, Technology and Research, Singapore.
authors.forename: Joo Chuan
authors.initials: JC
authors.lastname: Tong
authors.affiliation: Department of Pathology, Faculty of Medicine, University of Malaya, Malaysia.
authors.forename: Kum Thong
authors.initials: KT
authors.lastname: Wong
authors.affiliation: Cell and Molecular Immunology, Department of Medicine, Center for Molecular Medicine, Unit for Experimental Cardiovascular Research and Department of Neurology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Söderberg-Naucler
authors.affiliation: Cell and Molecular Immunology, Department of Medicine, Center for Molecular Medicine, Unit for Experimental Cardiovascular Research and Department of Neurology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Koon-Chu
authors.initials: KC
authors.lastname: Yaiw
mesh_terms: D001119:Arginase / Q000096:biosynthesis* / Q000235:genetics; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D003587:Cytomegalovirus / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000201:enzymology / Q000473:pathology / Q000821:virology; D018450:Disease Progression; D005909:Glioblastoma / Q000098:blood supply / Q000201:enzymology / Q000473:pathology / Q000821:virology*; D006801:Humans; D007150:Immunohistochemistry; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000473:pathology / Q000821:virology; D014162:Transfection; D015854:Up-Regulation
chemical_list: D001119:Arginase
keywords: arginase; cytomegalovirus; glioblastoma; treatment