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

In Hye Jung, Ga Lam Leem, Dawoon E. Jung, Min Hee Kim, Eun Young Kim, Se Hoon Kim, Hae Chul Park, Seung Woo Park

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

BackgroundOngoing 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.MethodsWe established transgenic zebrafish that overexpressed dominant-active (DA) human Akt1 or Rac1 G12V (DARac1) at ptf1a domain and investigated transgenic phenotypes and mechanisms leading to gliomagenesis.ResultsTransgene 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.ConclusionsThe zebrafish model reinforces the pivotal role of Akt signaling in gliomagenesis and suggests Rac1 as an important protein involved in progression.

Original languageEnglish
Pages (from-to)290-304
Number of pages15
JournalNeuro-Oncology
Volume15
Issue number3
DOIs
Publication statusPublished - 2013 Mar 1

Fingerprint

Zebrafish
Glioma
Survival
Fourth Ventricle
Catenins
Neoplasms
Epithelial-Mesenchymal Transition
Cyclin D1
Incidence
Cadherins
Cerebellum
Up-Regulation
Stem Cells
Down-Regulation
Embryonic Structures
Head
Cell Proliferation
Apoptosis
Phenotype
Genes

Keywords

  • Akt1
  • epithelial-mesenchymal transition
  • glioma
  • Rac1
  • transgenic zebrafish

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Clinical Neurology

Cite this

Jung, I. H., Leem, G. L., Jung, D. E., Kim, M. H., Kim, E. Y., Kim, S. H., ... Park, S. W. (2013). Glioma is formed by active Akt1 alone and promoted by active Rac1 in transgenic zebrafish. Neuro-Oncology, 15(3), 290-304. https://doi.org/10.1093/neuonc/nos387

Glioma is formed by active Akt1 alone and promoted by active Rac1 in transgenic zebrafish. / Jung, In Hye; Leem, Ga Lam; Jung, Dawoon E.; Kim, Min Hee; Kim, Eun Young; Kim, Se Hoon; Park, Hae Chul; Park, Seung Woo.

In: Neuro-Oncology, Vol. 15, No. 3, 01.03.2013, p. 290-304.

Research output: Contribution to journalArticle

Jung, IH, Leem, GL, Jung, DE, Kim, MH, Kim, EY, Kim, SH, Park, HC & Park, SW 2013, 'Glioma is formed by active Akt1 alone and promoted by active Rac1 in transgenic zebrafish', Neuro-Oncology, vol. 15, no. 3, pp. 290-304. https://doi.org/10.1093/neuonc/nos387
Jung, In Hye ; Leem, Ga Lam ; Jung, Dawoon E. ; Kim, Min Hee ; Kim, Eun Young ; Kim, Se Hoon ; Park, Hae Chul ; Park, Seung Woo. / Glioma is formed by active Akt1 alone and promoted by active Rac1 in transgenic zebrafish. In: Neuro-Oncology. 2013 ; Vol. 15, No. 3. pp. 290-304.
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abstract = "BackgroundOngoing 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.MethodsWe established transgenic zebrafish that overexpressed dominant-active (DA) human Akt1 or Rac1 G12V (DARac1) at ptf1a domain and investigated transgenic phenotypes and mechanisms leading to gliomagenesis.ResultsTransgene 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.ConclusionsThe zebrafish model reinforces the pivotal role of Akt signaling in gliomagenesis and suggests Rac1 as an important protein involved in progression.",
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AU - Jung, In Hye

AU - Leem, Ga Lam

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AU - Kim, Eun Young

AU - Kim, Se Hoon

AU - Park, Hae Chul

AU - Park, Seung Woo

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N2 - BackgroundOngoing 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.MethodsWe established transgenic zebrafish that overexpressed dominant-active (DA) human Akt1 or Rac1 G12V (DARac1) at ptf1a domain and investigated transgenic phenotypes and mechanisms leading to gliomagenesis.ResultsTransgene 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.ConclusionsThe zebrafish model reinforces the pivotal role of Akt signaling in gliomagenesis and suggests Rac1 as an important protein involved in progression.

AB - BackgroundOngoing 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.MethodsWe established transgenic zebrafish that overexpressed dominant-active (DA) human Akt1 or Rac1 G12V (DARac1) at ptf1a domain and investigated transgenic phenotypes and mechanisms leading to gliomagenesis.ResultsTransgene 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.ConclusionsThe zebrafish model reinforces the pivotal role of Akt signaling in gliomagenesis and suggests Rac1 as an important protein involved in progression.

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