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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, Libermann, Towia A., Raisanen, Jack M., Ashfaq, Raheela, Wong, Eric T., Wu, Julian, Elliott, Robert, Habib, Amyn A.·2006·Cancer Research
DOI 10.1158/0008-5472.can-05-2753

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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. Thus, our study provides a new insight into oncogenic signaling by EGFRvIII and improves our understanding of how autocrine loops are generated in glioma. (Cancer Res 2006; 66(2): 867-74)

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  • GGA1-3 regulate cell surface transport of α2B-adrenergic receptor and their inhibition decreases cell surface expression and attenuates downstream ERK1/2 signal transduction.

    “For example, GGA1-3 regulate the cell surface transport of α2B-adrenegic receptor (α2B-AR) - a G protein-coupled receptor – and their inhibition decreases the cell surface expression of α2B-AR and attenuates downstream signal transduction though ERK1/236.”

    From Integrative Genomic Analyses Identifies GGA2 as a Cooperative Driver of EGFR-Mediated Lung Tumorigenesis (2019) · cites this paper as [36]

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Metadata

Authors
Ramnarain, D. B., Park, S., Lee, D. Y., Hatanpaa, K. J., Scoggin, S. O., Otu, H., Libermann, T. A., Raisanen, J. M., Ashfaq, R., Wong, E. T., Wu, J., Elliott, R., & Habib, A. A.
Affiliations
  • 1Neurology and Departments of
  • 5Neurology and
  • 2Pathology,
  • 4Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas and Departments of
  • 7Genomics Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston Massachusetts
  • 6Neurosurgery and
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2006-01-15
Volume
66
Issue
2
Pages
867-874
ISSN
  • 0008-5472
  • 1538-7445
DOI
10.1158/0008-5472.can-05-2753
Cited by
140
References
0
Language
en

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