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Glioma is formed by active Akt1 alone and promoted by active Rac1 in transgenic zebrafish

Authors
 In Hye Jung  ;  Ga Lam Leem  ;  Dawoon E. Jung  ;  Min Hee Kim  ;  Eun Young Kim  ;  Se Hoon Kim  ;  Hae-Chul Park  ;  Seung Woo Park 
Citation
 NEURO-ONCOLOGY, Vol.15(3) : 290-304, 2013 
Journal Title
 NEURO-ONCOLOGY 
ISSN
 1522-8517 
Issue Date
2013
MeSH
Animals ; Animals, Genetically Modified ; Brain Neoplasms/genetics ; Brain Neoplasms/metabolism ; Brain Neoplasms/pathology* ; Embryo, Nonmammalian/metabolism ; Embryo, Nonmammalian/pathology ; Fluorescent Antibody Technique ; Gene Expression Regulation, Developmental ; Gene Expression Regulation, Neoplastic* ; Genes, Dominant ; Glioma/genetics ; Glioma/metabolism ; Glioma/pathology* ; Humans ; Immunoenzyme Techniques ; Proto-Oncogene Proteins c-akt/genetics ; Proto-Oncogene Proteins c-akt/metabolism* ; RNA, Messenger/genetics ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction ; Transcription Factors/metabolism ; Zebrafish/embryology ; Zebrafish/genetics* ; rac1 GTP-Binding Protein/genetics ; rac1 GTP-Binding Protein/metabolism*
Keywords
Animals ; Animals, Genetically Modified ; Brain Neoplasms/genetics ; Brain Neoplasms/metabolism ; Brain Neoplasms/pathology* ; Embryo, Nonmammalian/metabolism ; Embryo, Nonmammalian/pathology ; Fluorescent Antibody Technique ; Gene Expression Regulation, Developmental ; Gene Expression Regulation, Neoplastic* ; Genes, Dominant ; Glioma/genetics ; Glioma/metabolism ; Glioma/pathology* ; Humans ; Immunoenzyme Techniques ; Proto-Oncogene Proteins c-akt/genetics ; Proto-Oncogene Proteins c-akt/metabolism* ; RNA, Messenger/genetics ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction ; Transcription Factors/metabolism ; Zebrafish/embryology ; Zebrafish/genetics* ; rac1 GTP-Binding Protein/genetics ; rac1 GTP-Binding Protein/metabolism*
Abstract
Background Ongoing characterization of glioma has revealed that Akt signaling plays a crucial role in gliomagenesis. In mouse models, however, Akt alone was not sufficient to induce glioma. Methods We established transgenic zebrafish that overexpressed dominant-active (DA) human Akt1 or Rac1G12V (DARac1) at ptf1a domain and investigated transgenic phenotypes and mechanisms leading to gliomagenesis. Results Transgene expressions were spatiotemporally restricted without any developmental abnormality of embryos and persisted at cerebellum and medulla in adult zebrafish. DAAkt1 alone induced glioma (with visible bumps at the head), with incidences of 36.6% and 49% at 6 and 9 months, respectively. Histologically, gliomas showed various histologic grades, increased proliferation, and frequent invasion into the fourth ventricle. Preferential location of small tumors at periventricular area and coexpression of Her4 suggested that tumors originated from Ptf1a- and Her4-positive progenitor cells at ventricular zone. Gliomagenesis was principally mediated by activation of survival pathway through upregulation of survivin genes. Although DARac1 alone was incapable of gliomagenesis, when coexpressed with DAAkt1, gliomagenesis was accelerated, showing higher tumor incidences (62.0% and 73.3% at 6 and 9 months, respectively), advanced histologic grade, invasiveness, and shortened survival. DARac1 upregulated survivin2, cyclin D1, β-catenin, and snail1a but downregulated E-cadherin, indicating that DARac1 promotes gliomagenesis by enhancing proliferation, survival, and epithelial-to-mesenchymal transition. On pharmacologic tests, only Akt1/2 inhibitor effectively suppressed gliomagenesis, inhibited cellular proliferation, and induced apoptosis in established gliomas. Conclusions The zebrafish model reinforces the pivotal role of Akt signaling in gliomagenesis and suggests Rac1 as an important protein involved in progression.
Files in This Item:
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DOI
10.1093/neuonc/nos387
Appears in Collections:
1. College of Medicine (의과대학) > Medical Research Center (임상의학연구센터) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Min Hee(김민희)
Kim, Se Hoon(김세훈) ORCID logo https://orcid.org/0000-0001-7516-7372
Kim, Eun Young(김은영)
Park, Seung Woo(박승우) ORCID logo https://orcid.org/0000-0001-8230-964X
Leem, Ga Lam(임가람)
Jung, In Hye(정인혜)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/86650
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