Expression of eukaryotic initiation factor 4E and 4E binding protein 1 in colorectal carcinogenesis

Abstract

Cap dependent translation is mainly regulated at the level of the eukaryotic initiation factor 4E (eIF4E), the activity of which is controlled by phosphorylation and sequestration by its well established regulator, 4E binding protein 1 (4E-BP1). Both eIF4E and 4E-BP1 have been shown to be involved in the malignant progression of multiple human cancers, including colorectal cancer. However, the data on determining the expression of eIF4E, 4E-BP1 and their phosphorylated forms simultaneously in a single patient with colorectal cancer is lacking. Therefore the aim of our study was to explore the roles of these factors in colorectal carcinogenesis by immunohistostaining colorectal tissues (normal, low grade adenoma, high grade adenoma, and adenocarcinoma). Our results showed that the expression levels of eIF4E increased steadily as the cancer progressed from the case of benign dysplasia to an adenocarcinoma; all the while maintaining an unphosphorylated form. On the other hand, total expression levels of 4E-BP1 increased only in the premalignant state of the disease and decreased (but highly phosphorylated or inactivated) or abolished upon malignancy. Taken together, our findings suggest that strong correlations exist between the expression of eIF4E (not p-eIF4E) and tumor grade providing evidence that eIF4E expression plays a pivotal role in the malignant progression of colorectal cancer. Moreover, 4E-BP1 showed a bi-phasic level of expression during carcinogenesis, which is expressed only in hyperplasic or dysplastic tissues as an endogenous tumor suppressor molecule.

Keywords: 4E-BP1; Colorectal cancer; eIF4E; immunuhistochemistry; translational control.

Figure 1

Expression levels of eIF4E in a prototype colorectal tissue with different stage of lesion. A: Normal; B: Low grade adenoma; C: High grade adenoma; D: Adenocarcinoma.

Figure 2

Expression levels of 4E-BP1 in a prototype colorectal tissue with different stage of lesion. A: Normal; B: Low grade adenoma; C: High grade adenoma; D: Adenocarcinoma.

Figure 3

Expression levels of p4E-BP1 in a prototype colorectal tissue with different stage of lesion. A: Normal; B: Low grade adenoma; C: High grade adenoma; D: Adenocarcinoma.

Figure 4

Expression levels of 4E-BP1 and p4E-BP1 in adenocarcinoma tissues. The expression levels of 4E-BP1 (A, C) and the phosphorylated ser65 form (B, D) were showed from two patient samples.