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Human cytomegalovirus may promote tumour progression by upregulating arginase-2
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 30, 47221-47231 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Impact Journals LLC , 2016. Vol. 7, no 30, 47221-47231 p.
Keyword [en]
Arginase, Cytomegalovirus, Glioblastoma, Treatment, arginase 2, gelatinase A, gelatinase B, hydrolase inhibitor, n (omega) hydroxy nor arginine, nitric oxide synthase, small interfering RNA, unclassified drug, vasculotropin, Article, bioinformatics, cancer genetics, cancer growth, cancer survival, cancer tissue, cell invasion, cell migration, cell proliferation, cellular parameters, controlled study, enzyme activity, enzyme induction, enzyme regulation, ex vivo study, glioblastoma cell line, human, human cell, Human cytomegalovirus, human tissue, immunohistochemistry, in vitro study, nonhuman, protein expression, upregulation, vasculogenic mimicry, virus carcinogenesis, virus cell interaction
National Category
Genetics Medical Engineering
Identifiers
URN: urn:nbn:se:kth:diva-195449DOI: 10.18632/oncotarget.9722ISI: 000385413000032ScopusID: 2-s2.0-84982850648OAI: oai:DiVA.org:kth-195449DiVA: diva2:1046788
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceSwedish Cancer Society
Note

QC 20161115

Available from: 2016-11-15 Created: 2016-11-03 Last updated: 2016-11-17Bibliographically approved

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