peIF4E as an independent prognostic factor and a potential therapeutic target in diffuse infiltrating astrocytomas

Abstract

Malignant transformation in tumors is a complex process requiring accumulation of numerous oncogenic abnormalities. Brain tumors show considerable phenotypic and genetic heterogeneity. In a series comprising diffuse infiltrating astrocytomas (DIA) and reactive gliosis, we investigated the main factors associated with signaling pathways. We assessed expression levels and their association with tumor progression and survival. We studied 19 grade II astrocytomas, 25 anaplastic astrocytomas (grade III), 60 glioblastomas (grade IV), and 15 cases of reactive gliosis. Epidermal growth factor receptor (EGFR), pMAPK, 4E‐BP1, p4E‐BP1, pS6, eIF4E, and peIF4E expression levels were evaluated using immunohistochemistry. Expression levels were semiquantitatively evaluated using a histoscore. Immunohistochemistry and PCR were used for IDH1 mutations. Statistical analysis was based on the following tests: chi‐square, Student's t, Pearson correlation, Spearman's rho, and Mann–Whitney; ROC and Kaplan–Meier curves were constructed. A significant increase was observed between grades for expression of total and phosphorylated 4E‐BP1 and for eIF4E, Ki67, EGFR, and cyclin D1. Although expression of EGFR, eIF4E, and Ki67 correlated with survival, only peIF4E was an independent predictor of survival in the multivariate analysis. Combining the evaluation of different proteins enables us to generate helpful diagnostic nomograms. In conclusion, cell signaling pathways are activated in DIAs; peIF4E is an independent prognostic factor and a promising therapeutic target. Joint analysis of the expression of 4E‐BP1 and peIF4E could be helpful in the diagnosis of glioblastoma multiforme in small biopsy samples.

Cytoplasmic cyclin D1 regulates glioblastoma dissemination

“…Using patient‐derived glioma TMAs, we confirmed that Ccnd1 expression is higher in GBM than in grade I and II astrocytoma biopsies (Figure A,B) . However, only a small proportion of cells showed clear cytoplasmic signal for Ccnd1 (Figure C).…”

Genetic variants in the TGFβ-signaling pathway influence expression of miRNAs in colon and rectal normal mucosa and tumor tissue

“…eIF4E is essential for ribosomal recruitment and the initiation of translation [33]; eIF4E binds eIF4A and eIF4G to form the eIF4F complex that binds target mRNAs. In this system, eIF4E appears to be key in the regulation of translation initiation, as it physically binds the mRNA and is the least abundant initiation factor [34]; the interface of these genes with miRNAs is supported given the role of miRNAs is post-transcriptional. It has a sole phosphorylation site that interacts with either eIF4G or non-phosphorylated 4E-BP1; the PI3-Akt-mTOR pathway phosphorylates 4E-BP1 so that it releases eIF4E, allowing binding to eIF4G [34].…”

“…In this system, eIF4E appears to be key in the regulation of translation initiation, as it physically binds the mRNA and is the least abundant initiation factor [34]; the interface of these genes with miRNAs is supported given the role of miRNAs is post-transcriptional. It has a sole phosphorylation site that interacts with either eIF4G or non-phosphorylated 4E-BP1; the PI3-Akt-mTOR pathway phosphorylates 4E-BP1 so that it releases eIF4E, allowing binding to eIF4G [34]. Thus eIF4E is important in the convergence of the TGF-β and Akt pathways, and its dysregulation is believed to be an important downstream regulator of Akt's action in tumorigenesis [6].…”

Differential Response of Glioma Stem Cells to Arsenic Trioxide Therapy Is Regulated by MNK1 and mRNA Translation

“…MNK activation and subsequent phosphorylation of eIF4E are negative prognostic factors for several cancers including malignant gliomas (44–47). In addition to regulating cap-dependent mRNA translation, eIF4E also promotes nuclear export of specific eIF4E-sensitive oncogenic mRNAs through a process that is activated by MNK-mediated eIF4E phosphorylation (48, 49).…”