Correlation between EGFR amplification and the expression of microRNA-200c in primary glioblastoma multiforme.

Eva Serna,Robert C Callaghan,Horacio Martinetto,Concha Lopez-Gines,Rosario Gil-Benso,Aurelia Gregori-Romero,Jose Gonzalez-Darder,Daniel Monleon,Lisandra Muñoz-Hidalgo,Miguel Cerda-Nicolas,Ilya Ulasov

doi:10.1371/journal.pone.0102927

Abstract

Extensive infiltration of the surrounding healthy brain tissue is a critical feature in glioblastoma. Several miRNAs have been related to gliomagenesis, some of them related with the EGFR pathway. We have evaluated whole-genome miRNA expression profiling associated with different EGFR amplification patterns, studied by fluorescence in situ hybridization in tissue microarrays, of 30 cases of primary glioblastoma multiforme, whose clinicopathological and immunohistochemical features have also been analyzed. MicroRNA-200c showed a very significant difference between tumors having or not EGFR amplification. This microRNA plays an important role in epithelial-mesenchymal transition, but its implication in the behavior of glioblastoma is largely unknown. With respect to EGFR status our cases were categorized into three groups: high level EGFR amplification, low level EGFR amplification, and no EGFR amplification. Our results showed that microRNA-200c and E-cadherin expression are down-regulated, while ZEB1 is up-regulated, when tumors showed a high level of EGFR amplification. Conversely, ZEB1 mRNA expression levels were significantly lower in the group of tumors without EGFR amplification. Tumors with a low level of EGFR amplification showed ZEB1 expression levels comparable to those detected in the group with a high level of amplification. In this study we provide what is to our knowledge the first report of association between microRNA-200c and EGFR amplification in glioblastomas.

Highlights

Glioblastoma multiforme (GBM) is the most common and most aggressive malignant primary brain tumor in humans
According to the Epidermal growth factor receptor (EGFR) status, gene copy number and type of amplification, tumors have been categorized into three groups [7]: GBM with high level of EGFR amplification as double minutes, in which the fraction of cells with amplification is higher than 20% and with more than 25 EGFR signals per cell, GBM with low level of EGFR amplification as insertions into different loci on chromosome 7, with a 5–20% of cells with amplification and less than 20 EGFR signals per cell, and GBM without EGFR amplification
In the present study we evaluated whole-genome miRNA expression profiling in samples of human GBMs associated with different EGFR amplification patterns

Summary

Introduction

Glioblastoma multiforme (GBM) is the most common and most aggressive malignant primary brain tumor in humans. The growth and invasive nature of GBM are promoted by dysregulation of multiple signaling pathways [3]. Epidermal growth factor receptor (EGFR) amplification, observed in about 35–70% of GBMs, constitutes a lesion signature for these tumors [4,5,6]. According to the EGFR status, gene copy number and type of amplification, tumors have been categorized into three groups [7]: GBM with high level of EGFR amplification as double minutes (dmin), in which the fraction of cells with amplification is higher than 20% and with more than 25 EGFR signals per cell, GBM with low level of EGFR amplification as insertions into different loci on chromosome 7, with a 5–20% of cells with amplification and less than 20 EGFR signals per cell, and GBM without EGFR amplification

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Conclusion