The early growth response gene EGR-1 behaves as a suppressor gene that is down-regulated independent of ARF/Mdm2 but not p53 alterations in fresh human gliomas

A. Calogero, A. Arcella, G. De Gregorio, A. Porcellini, D. Mercola, C. Liu, V. Lombari, M. Zani, G. Giannini, F. M. Gagliardi, R. Caruso, A. Gulino, L. Frati, G. Ragona

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Abstract

Purpose: EGR-1 is an immediate early gene with diverse functions that include the suppression of growth. EGR-1 is down-regulated many cancer cell types, suggesting a tumor suppressor role, and may critically involve the p53 pathway. The aim of this work was to measure the expression of EGR-1 and the p16/INK4a/ARF-Mdm2-p53 pathway status in fresh human gliomas. Experimental Design: Thirty-one human gliomas with different grades of malignancy were investigated for Egr-1 mRNA and the protein expression, frequency, and spectrum of p53 gene mutations, mdm2 gene amplification, and p16/INK4a/ARF allele loss. Results: The amplification of Mdm2 and the deletion of the p16/INK4a gene was found in 3 and 5 cases, respectively, whereas mutations of p53, including two novel mutations, were observed in 10 other cases. The three types of changes occurred strictly mutually exclusively, emphasizing that these genes operate in a common pathway critical to glioma progression. EGR-1 mRNA was significantly down-regulated in astrocytomas (14.7 ± 5.1%) and in glioblastomas (33.6 ± 10.0%) versus normal brain. Overall, EGR-1 mRNA was strongly suppressed (average, 15.2 ± 13.9%) in 27 of 31 cases (87%), independent of changes in p16/INK4a/ARF and Mdm2; whereas 4 of 31 cases with residual EGR-1 expression as well as the highest EGR-1 variance segregated with p53 mutations. Immunohistochemical analyses confirmed the suppression of EGR-1 protein. Conclusions: These results indicate that EGR-1 is commonly suppressed in gliomas independent of p16/INK4a/ARF and Mdm2 and that suppression is less crucial in tumors bearing p53 mutations, and these results implicate an EGR-1 growth regulatory mechanism as a target of inactivation during tumor progression.

Original languageEnglish
Pages (from-to)2788-2796
Number of pages9
JournalClinical Cancer Research
Volume7
Issue number9
Publication statusPublished - 2001

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Calogero, A., Arcella, A., De Gregorio, G., Porcellini, A., Mercola, D., Liu, C., Lombari, V., Zani, M., Giannini, G., Gagliardi, F. M., Caruso, R., Gulino, A., Frati, L., & Ragona, G. (2001). The early growth response gene EGR-1 behaves as a suppressor gene that is down-regulated independent of ARF/Mdm2 but not p53 alterations in fresh human gliomas. Clinical Cancer Research, 7(9), 2788-2796.