Differential gene expression analysis reveals generation of an autocrine loop by a mutant epidermal growth factor receptor in glioma cells

Deepti B. Ramnarain, Seongmi Park, Diana Y. Lee, Kimmo J. Hatanpaa, Shane O. Scoggin, Hasan H Otu, Towia A. Libermann, Jack M. Raisanen, Raheela Ashfaq, Eric T. Wong, Julian Wu, Robert Elliott, Amyn A. Habib

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Abstract

The epidermal growth factor receptor (EGFR) gene is commonly amplified and rearranged in glioblastoma multiforme leading to overexpression of wild-type and mutant EGFRs. Expression of wild-type EGFR ligands, such as transforming growth factor-α (TGF-α) or heparin-binding EGF (HB-EGF), is also often increased in gliomas resulting in an autocrine loop that contributes to the growth autonomy of glioma cells. Glioblastoma multiformes express a characteristic EGFR mutant (EGFRvIII, de 2-7) that does not bind ligand, signals constitutively, and is more tumorigenic than the wild-type receptor. However, the downstream signals that mediate this increased tumorigenicity are not well understood. We hypothesized that signals induced specifically by EGFRvIII and not the wild-type receptor are more likely to mediate its increased tumorigenic activity and examined the gene expression profiles resulting from inducible expression of comparable levels of either wild-type EGFR or EGFRvIII in a U251-MG glioma cell line. Expression of EGFRvIII resulted in specific up-regulation of a small group of genes. Remarkably, all these genes, which include TGFA, HB-EGF, EPHA2, IL8, MAP4K4, FOSL1, EMP1, and DUSP6, influence signaling pathways known to play a key role in oncogenesis and function in interconnected networks. Increased expression of EGFRvIII-induced genes was validated by real-time PCR. The mutant receptor does not bind ligand, and EGFRvIII-induced expression of TGF-α and HB-EGF suggests that EGFRvIII plays a role in generating an autocrine loop using the wild-type EGFR in glioma. It also raises the possibility that EGFRvIII may signal, at least in part, through the wild-type receptor. Indeed, we show that inhibiting the activity of HB-EGF, a potent mitogen, with neutralizing antibodies reduces cell proliferation induced by expression of EGFRvIII. This suggests that the EGFRvIII-HB-EGF-wild-type EGFR autocrine loop plays an important role in signal transduction by EGFRvIII in glioma cells. We also show by immunohistochemistry that HB-EGF expression correlates with the presence of EGFRvIII in glioblastoma multiforme.

Original languageEnglish (US)
Pages (from-to)867-874
Number of pages8
JournalCancer Research
Volume66
Issue number2
DOIs
StatePublished - Jan 15 2006

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Epidermal Growth Factor Receptor
Glioma
Gene Expression
Epidermal Growth Factor
Heparin
Glioblastoma
Transforming Growth Factors
Ligands
epidermal growth factor receptor VIII
Genes
erbB-1 Genes
Neutralizing Antibodies
Interleukin-8
Mitogens
Transcriptome
Real-Time Polymerase Chain Reaction
Signal Transduction
Carcinogenesis
Up-Regulation
Immunohistochemistry

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Differential gene expression analysis reveals generation of an autocrine loop by a mutant epidermal growth factor receptor in glioma cells. / Ramnarain, Deepti B.; Park, Seongmi; Lee, Diana Y.; Hatanpaa, Kimmo J.; Scoggin, Shane O.; Otu, Hasan H; Libermann, Towia A.; Raisanen, Jack M.; Ashfaq, Raheela; Wong, Eric T.; Wu, Julian; Elliott, Robert; Habib, Amyn A.

In: Cancer Research, Vol. 66, No. 2, 15.01.2006, p. 867-874.

Research output: Contribution to journalArticle

Ramnarain, DB, Park, S, Lee, DY, Hatanpaa, KJ, Scoggin, SO, Otu, HH, Libermann, TA, Raisanen, JM, Ashfaq, R, Wong, ET, Wu, J, Elliott, R & Habib, AA 2006, 'Differential gene expression analysis reveals generation of an autocrine loop by a mutant epidermal growth factor receptor in glioma cells', Cancer Research, vol. 66, no. 2, pp. 867-874. https://doi.org/10.1158/0008-5472.CAN-05-2753
Ramnarain, Deepti B. ; Park, Seongmi ; Lee, Diana Y. ; Hatanpaa, Kimmo J. ; Scoggin, Shane O. ; Otu, Hasan H ; Libermann, Towia A. ; Raisanen, Jack M. ; Ashfaq, Raheela ; Wong, Eric T. ; Wu, Julian ; Elliott, Robert ; Habib, Amyn A. / Differential gene expression analysis reveals generation of an autocrine loop by a mutant epidermal growth factor receptor in glioma cells. In: Cancer Research. 2006 ; Vol. 66, No. 2. pp. 867-874.
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