High metallothionein predicts poor survival in glioblastoma multiforme.

Ruty Mehrian-Shai,Michal Yalon,Amos J Simon,Itai Moshe,Amos Toren,Tatyana Pismenyuk,Eran Eyal,Shlomi Constantini

doi:10.1186/s12920-015-0137-6

Abstract

BackgroundGlioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor. Even with vigorous surgery, radiation and chemotherapy treatment, survival rates of GBM are very poor and predictive markers for prognosis are currently lacking.MethodsWe performed whole genome expression studies of 67 fresh frozen untreated GBM tumors and validated results by 210 GBM samples’ expression data from The Cancer Genome Atlas.Results and discussionHere we show that in GBM patients, high metallothionein (MT) expression is associated with poor survival whereas low MT levels correspond to good prognosis. Furthermore we show that in U87 GBM cell line, p53 is found to be in an inactive mutant-like conformation concurrently with more than 4 times higher MT3 expression level than normal astrocytes and U251GBM cell line. We then show that U87- p53 inactivity can be rescued by zinc (Zn).ConclusionsTaken together, these data suggest that MT expression may be a potential novel prognostic biomarker for GBM, and that U87 cells may be a good model for patients with non active WT p53 resulting from high levels of MTs.

Highlights

Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor
In this study we report that in GBM patients, high metallothionein (MT) expression is associated with poor survival whereas low MT levels correspond to good prognosis
All MTs that were quantified in this study had significantly higher mean expression intensity in short survival patients compared to long survival patients (Fig. 5a) (3.6 times for MT1E, 2.5 for MT1F, 4.2 times for MT1H, 3.2 times for MT1M, 1.8 times for MT1x, 3.9 times for metallothionein 2A (MT2A) and 1.5 times for MT3)

Summary

Methods

Human subjects and cell lines: 67 fresh frozen untreated GBM tumors and seven postmortem normal brain samples (subcortical white matter) from UCLA tumor bank were used for the discovery set. Gene expression profiling studies of these samples were generated according to standard Affymetrix protocols. After the discovery of genes that are predictive of survival, their mean expression value were plotted and compared between samples. The value for normal sample expression is plotted on the expression plot for base line orientation. For the 210 TCGA GBM samples Affymetrix HT Human Genome U133 expression data were loaded from TCGA data portal (https://tcga-data.nci.nih.gov/tcga). Quantitative real time PCR: qRT-PCR experiments of human-derived GBM cell lines U251, U87 and normal human astrocytes were performed. ZnCl2 (Sigma-Aldrich) was added at final concentration of 100 μM

Background

Results

Discussion

Conclusions