Prognostic significance of co-overexpression of the EGFR/IGFBP-2/HIF-2A genes in astrocytomas

Abstract

Overexpression of the EGFR, IGFBP-2 and HIF-2A genes has been observed in high-grade astrocytomas and these genes seem to be functionally related to one another. This study aimed to define the profile of their expressions, interactions and correlation with clinical features and prognostic significance in microdissected tumor samples from 84 patients with astrocytomas of different grades and from 6 white matter non-neoplasic brain tissue sample. EGFR, IGFBP-2 and HIF-2A gene expression levels were analyzed by quantitative real-time PCR and differed significantly between grades I-IV astrocytic tumors (P < 0.0001, P < 0.0001 and P: 0.0013, respectively) when analyzed by the Kruskal-Wallis test. Grade I astrocytomas presented gene expression levels similar to those encountered in samples of microdissected white matter of non-neoplastic brain tissue Overexpression of the EGFR, IGFBP-2 and HIF-2A genes was significantly associated with lower 2-year survival (P: 0.009, P: 0.0002 and P: 0.008, respectively). Co-overexpression of these genes was strongly associated with high-grade gliomas and lower survival in univariate (P < 0.0001) and multivariate (P: 0.009) analysis, suggesting that the co-expression of the EGFR/IGFBP-2/HIF-2A pathway genes may have a more important clinical and biological impact than the expression of each individual gene alone. These data support the existence of a common pathway involving these genes that could contribute to the design of new target treatments.

Plasma IGFBP-2 levels predict clinical outcomes of patients with high-grade gliomas

“…22 Previous studies have shown that increased IGFBP-2 expression in a tumor promotes glioma cell migration and invasion through activation of the matrix metalloproteinase 2 protein and integrin pathway [23][24][25][26][27] and that this increased expression is associated with glioma malignancy and poor survival of glioma patients. 12,13,16,18,[28][29][30][31][32][33] Attenuation of IGFBP-2 by the tumor suppressor protein IIp45 or using small interfering RNA resulted in decreased cell motility and invasion. 23,26 Recently, IGFBP-2 has been found to be a "driver" oncogene for glioma development and progression.…”

The Role of Hypoxia-Inducible Factors in Cancer Resistance

“…Consistent with this, it has been reported that HIF2α drives tumor progression in renal carcinoma cells in which there is a gradual shift from HIF1α to HIF2α expression with increasing tumor grade [83]. HIF2α (but not HIF1α) has been shown to cooperate with a number of oncoproteins frequently deregulated in cancer such as c-Myc, epidermal growth factor receptor (EGFR), and K-Ras [84][85][86] and has been linked to increased tumor aggressiveness through the promotion of self-renewal and epithelial to mesenchymal transition (EMT). In addition, Koh et al [80] identified the hypoxia-associated factor (HAF) as an E3 ubiquitin ligase that binds to and ubiquitinates HIF1α by an oxygen-and pVHL-independent mechanism, targeting HIF1α for proteasomal degradation.…”

Role of H-Ferritin in Radiosensitivity of Human Glioma Cells

“…The relationship between HIFs level and cancer progression has been investigated in many cancer types, and has even raised the prospect of targeting HIFs as a possible cancer therapy [26]. Specifically, HIF-2α is thought to serve as a crucial factor in glioma cell survival and a prognostic marker in glioma patients [27,38]. Our data reveal that the HIF-2α level in glioma cells is decreased after down-regulation of H-ferritin (Figure 3c).…”