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Review
. 2010 Jun 30;15(7):4670-8.
doi: 10.3390/molecules15074670.

Ribozyme-mediated inhibition of 801-bp deletion-mutant epidermal growth factor receptor mRNA expression in glioblastoma multiforme

Georg Karpel-Massler  1 , Christian Rainer Wirtz, Marc-Eric Halatsch
Affiliations
Review

Ribozyme-mediated inhibition of 801-bp deletion-mutant epidermal growth factor receptor mRNA expression in glioblastoma multiforme

Georg Karpel-Massler et al. Molecules. .

Abstract

The epidermal growth factor receptor (HER1/EGFR) is known to be disregulated in a large subgroup of glioblastoma multiforme cases. Disregulation of HER1/EGFR is related to malignant transformation and tumor growth in various human cancers, including malignant glioma. One mechanism that may lead to disregulated HER1/EGFR signaling is the intrinsic alteration of the receptor structure due to mutational changes. The most common mutant form of HER1/EGFR, named variant III (EGFRvIII), results from an 801 bp in-frame deletion in the DNA sequence encoding the extracellular ligand-binding domain. Independent of ligand-binding, EGFRvIII is constitutively activated and beyond external control. Since its cellular expression was shown to relate enhanced tumorigenicity, various therapeutic strategies were developed to target EGFRvIII, including monoclonal antibodies, vaccination therapies and small-molecule tyrosine kinase inhibitors. In this review, we focus on ribozyme-mediated inhibition of EGFRvIII messenger RNA expression as a gene therapeutic approach for EGFRvIII-expressing glioblastoma multiforme.

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Figures

Figure 1
Figure 1
Basic structure of the wtHER1/EGFR and the EGFRvIII genes, the latter being characterized by a deletion of exons 2-7 comprising 801 basepairs. As a result, a new glycine codon is formed at the fusion junction.
Figure 2
Figure 2
Schematic overview on the mechanism underlying ribozyme-mediated inhibition of EGFRvIII gene expression and subsequent downregulation of EGFRvIII-mediated signaling.
Figure 3
Figure 3
Illustration of the molecular interaction between the sCYMV1-derived hairpin ribozyme and EGFRvIII mRNA (substrate). The cleavage site is indicated by an arrow.
See this image and copyright information in PMC

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