Abstract
Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. A variety of targeted agents are being tested in the clinic including cancer vaccines, immunotoxins, antibodies and T cell immunotherapy for GBM. We have previously reported that IL-13 receptor subunits α1 and α2 of IL-13R complex are overexpressed in GBM. We are investigating the significance of IL-13Rα1 and α2 expression in GBM tumors. In order to elucidate a possible relationship between IL-13Rα1 and α2 expression with severity and prognoses of subjects with GBM, we analyzed gene expression (by microarray) and clinical data available at the public The Cancer Genome Atlas (TCGA) database (Currently known as Global Data Commons). More than 40% of GBM samples were highly positive for IL-13Rα2 mRNA (Log2 ≥ 2) while only less than 16% samples were highly positive for IL-13Rα1 mRNA. Subjects with high IL-13Rα1 and α2 mRNA expressing tumors were associated with a significantly lower survival rate irrespective of their treatment compared to subjects with IL-13Rα1 and α2 mRNA negative tumors. We further observed that IL-13Rα2 gene expression is associated with GBM resistance to temozolomide (TMZ) chemotherapy. The expression of IL-13Rα2 gene did not seem to correlate with the expression of genes for other chains involved in the formation of IL-13R complex (IL-13Rα1 or IL-4Rα) in GBM. However, a positive correlation was observed between IL-4Rα and IL-13Rα1 gene expression. The microarray data of IL-13Rα2 gene expression was verified by RNA-Seq data. In depth analysis of TCGA data revealed that immunosuppressive genes (such as FMOD, CCL2, OSM, etc.) were highly expressed in IL-13Rα2 positive tumors, but not in IL-13Rα2 negative tumors. These results indicate a direct correlation between high level of IL-13R mRNA expression and poor patient prognosis and that immunosuppressive genes associated with IL-13Rα2 may play a role in tumor progression. These findings have important implications in understanding the role of IL-13R in the pathogenesis of GBM and potentially other cancers.
Highlights
Glioblastoma multiforme (GBM) is a devastating brain tumor with extremely poor prognosis because of its diffusive and infiltrative nature, which is marked cytological heterogeneity
These results suggest that IL-13Rα2 gene expression may be associated with GBM malignancy grade (Supplementary Fig S5)
We demonstrate that GBM tumors can be classified into three different distinct groups based on the analysis of gene expression data from 428 glioma subjects at the The Cancer Genome Atlas (TCGA) database for IL-13R (α1 and α2) gene expression
Summary
Glioblastoma multiforme (GBM) is a devastating brain tumor with extremely poor prognosis because of its diffusive and infiltrative nature, which is marked cytological heterogeneity. It is one of the most aggressive and common malignant brain tumors accounting for more than 50% of all gliomas [1]. Three glioblastoma subtypes were defined based on patient prognosis and gene expression. Gene expression studies from The Cancer Genome Atlas (TCGA) dataset defined four distinct glioblastoma subclasses, including proneural, neural, classical, and mesenchymal [4]. Kim et al classified GBMs into three prognostic groups, which were different from the previously identified subtypes, and identified a 42 probe set of gene signatures, which associated with tumor aggressiveness and related with the epithelial-mesenchymal transition (EMT) process [5]
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