Reciprocal Activation of Transcription Factors Underlies the Dichotomy between Proliferation and Invasion of Glioma Cells

Harshil D. Dhruv, Wendy S. McDonough Winslow, Brock Armstrong, Serdar Tuncali, Jenny Eschbacher, Kerri Kislin, Joseph C Loftus, Nhan Tran, Michael E. Berens

Research output: Contribution to journalArticle

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Abstract

Histology of malignant glioma depicts dense proliferative areas rich in angiogenesis as well as dissemination of neoplastic cells into adjacent brain tissue. Although the mechanisms that trigger transition from proliferative to invasive phenotypes are complex, the dichotomy of cell proliferation and migration, the "Go or Grow" hypothesis, argues for specific and coordinated regulation of these phenotypes. We investigated transcriptional elements that accompany the phenotypes of migration and proliferation, and consider the therapeutic significance of the "Go or Grow" hypothesis. Interrogation of matched core and rim regions from human glioblastoma biopsy specimens in situ (n = 44) revealed higher proliferation (Ki67 labeling index) in cells residing at the core compared to the rim. Profiling activated transcription factors in a panel of migration-activated versus migration-restricted GBM cells portrayed strong NF-κB activity in the migratory cell population. In contrast, increased c-Myc activity was found in migration-restricted proliferative cells. Validation of transcriptional activity by NF-κB- or c-Myc-driven GFP or RFP, respectively, showed an increased NF-κB activity in the active migrating cells, whereas the proliferative, migration restricted cells displayed increased c-Myc activity. Immunohistochemistry on clinical specimens validated a robust phosphorylated c-Myc staining in tumor cells at the core, whereas increased phosphorylated NF-κB staining was detected in the invasive tumor cells at the rim. Functional genomics revealed that depletion of c-Myc expression by siRNA oligonucleotides reduced cell proliferation in vitro, but surprisingly, cell migration was enhanced significantly. Conversely, inhibition of NF-κB by pharmacological inhibitors, SN50 or BAY-11, decreased both cell migration in vitro and invasion ex vivo. Notably, inhibition of NF-κB was found to have no effect on the proliferation rate of glioma cells. These findings suggest that the reciprocal and coordinated suppression/activation of transcription factors, such as c-Myc and NF-κB may underlie the shift of glioma cells from a "growing-to-going" phenotype.

Original languageEnglish (US)
Article numbere72134
JournalPLoS One
Volume8
Issue number8
DOIs
StatePublished - Aug 15 2013

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Glioma
Transcription Factors
transcription factors
Chemical activation
Cells
Cell proliferation
Tumors
Histology
Biopsy
cell movement
Cell Movement
cells
phenotype
Oligonucleotides
Labeling
Small Interfering RNA
Brain
Phenotype
Tissue
cell proliferation

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Dhruv, H. D., McDonough Winslow, W. S., Armstrong, B., Tuncali, S., Eschbacher, J., Kislin, K., ... Berens, M. E. (2013). Reciprocal Activation of Transcription Factors Underlies the Dichotomy between Proliferation and Invasion of Glioma Cells. PLoS One, 8(8), [e72134]. https://doi.org/10.1371/journal.pone.0072134

Reciprocal Activation of Transcription Factors Underlies the Dichotomy between Proliferation and Invasion of Glioma Cells. / Dhruv, Harshil D.; McDonough Winslow, Wendy S.; Armstrong, Brock; Tuncali, Serdar; Eschbacher, Jenny; Kislin, Kerri; Loftus, Joseph C; Tran, Nhan; Berens, Michael E.

In: PLoS One, Vol. 8, No. 8, e72134, 15.08.2013.

Research output: Contribution to journalArticle

Dhruv, HD, McDonough Winslow, WS, Armstrong, B, Tuncali, S, Eschbacher, J, Kislin, K, Loftus, JC, Tran, N & Berens, ME 2013, 'Reciprocal Activation of Transcription Factors Underlies the Dichotomy between Proliferation and Invasion of Glioma Cells', PLoS One, vol. 8, no. 8, e72134. https://doi.org/10.1371/journal.pone.0072134
Dhruv HD, McDonough Winslow WS, Armstrong B, Tuncali S, Eschbacher J, Kislin K et al. Reciprocal Activation of Transcription Factors Underlies the Dichotomy between Proliferation and Invasion of Glioma Cells. PLoS One. 2013 Aug 15;8(8). e72134. https://doi.org/10.1371/journal.pone.0072134
Dhruv, Harshil D. ; McDonough Winslow, Wendy S. ; Armstrong, Brock ; Tuncali, Serdar ; Eschbacher, Jenny ; Kislin, Kerri ; Loftus, Joseph C ; Tran, Nhan ; Berens, Michael E. / Reciprocal Activation of Transcription Factors Underlies the Dichotomy between Proliferation and Invasion of Glioma Cells. In: PLoS One. 2013 ; Vol. 8, No. 8.
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