Identification of expressed genes characterizing long-term survival in malignant glioma patients

Abstract

Better understanding of the underlying biology of malignant gliomas is critical for the development of early detection strategies and new therapeutics. This study aimed to define genes associated with survival. We investigated whether genes coupled with a class prediction model could be used to define subgroups of high-grade gliomas in a more objective manner than standard pathology. RNAs from 29 malignant gliomas were analysed using Agilent microarrays. We identified 21 genes whose expression was most strongly and consistently related to patient survival based on univariate proportional hazards models. In six out of 10 genes, changes in gene expression were validated by quantitative real-time PCR. After adjusting for clinical covariates based on a multivariate analysis, we finally obtained a statistical significance level for DDR1 (discoidin domain receptor family, member 1), DYRK3 (dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 3) and KSP37 (Ksp37 protein). In independent samples, it was confirmed that DDR1 protein expression was also correlated to the prognosis of glioma patients detected by immunohistochemical staining. Furthermore, we analysed the efficacy of the short interfering RNA (siRNA)-mediated inhibition of DDR1 mRNA synthesis in glioma cell lines. Cell proliferation and invasion were significantly suppressed by siRNA against DDR1. Thus, DDR1 can be a novel molecular target of therapy as well as an important predictive marker for survival in patients with glioma. Our method was effective at classifying highgrade gliomas objectively, and provided a more accurate predictor of prognosis than histological grading.

EphA4 promotes cell proliferation and migration through a novel EphA4-FGFR1 signaling pathway in the human glioma U251 cell line

“…The microarray raw data and clinical features has been submitted to Gene Expression Omnibus 5 (accession no. GSE4381) in our previous report (31).…”

The dark side of a tumor suppressor: anti-apoptotic p53

“…144 It appears though that this tyrosine kinase receptor may play a role in the progression of certain malignancies as DDR1 was found overexpressed in various carcinomas 145 and high DDR1 expression correlated negatively with survival in several malignant glioma patients. 146 Cyclooxygenase 2. Finally, either dependent on the HB-EGF-induced activation of the ras/raf/MAPK pathway or in cooperation with NF-kB, p53 induces expression of the cyclooxygenase 2 (Cox-2) gene following exposure to various DNA-damaging agents.…”

Discoidin domain receptor 1: New star in cancer-targeted therapy and its complex role in breast carcinoma (Review)

“…Regarding the role of DDR1 in invasion, accumulating evidence produced with matrigel invasion assays indicates that DDR1 can promote invasion in a number of types of human cancer cell line, including breast (56), lung (8), prostate (9), pituitary adenoma (67), hepatocellular carcinoma (14) and glioma (68,69). The pro-invasive function of DDR1 may be mediated by the upregulation of the expression of MMPs, particularly MMP-2 and MMP-9.…”