Dysregulation of Translation Factors EIF2S1, EIF5A and EIF6 in Intestinal-Type Adenocarcinoma (ITAC)

Abstract

Intestinal-type adenocarcinoma (ITAC) is a rare cancer of the nasal cavity and paranasal sinuses that occurs sporadically or secondary to exposure to occupational hazards, such as wood dust and leather. Eukaryotic translation initiation factors have been described as promising targets for novel cancer treatments in many cancers, but hardly anything is known about these factors in ITAC. Here we performed in silico analyses, evaluated the protein levels of EIF2S1, EIF5A and EIF6 in tumour samples and non-neoplastic tissue controls obtained from 145 patients, and correlated these results with clinical outcome data, including tumour site, stage, adjuvant radiotherapy and survival. In silico analyses revealed significant upregulation of the translation factors EIF6 (ITGB4BP), EIF5, EIF2S1 and EIF2S2 (p < 0.05) with a higher arithmetic mean expression in ITAC compared to non-neoplastic tissue (NNT). Immunohistochemical analyses using antibodies against EIF2S1 and EIF6 confirmed a significantly different expression at the protein level (p < 0.05). In conclusion, this work identifies the eukaryotic translation initiation factors EIF2S1 and EIF6 to be significantly upregulated in ITAC. As these factors have been described as promising therapeutic targets in other cancers, this work identifies candidate therapeutic targets in this rare but often deadly cancer.

Keywords: biomarkers; sinonasal adenocarcinoma of the intestinal type (ITAC); translation factors.

Figure 1

Significant Wilcoxon p-values of the translation factors (p < 0.05). Each factor was compared against the same factor between the groups ITAC and NNT in the dataset GSE17433. Black bars indicate that the arithmetic mean of the first group (ITAC) was higher than the arithmetic mean of the second group (NNT) and white bars indicate the opposite. ** indicate a p-value < 0.01, * indicates a p-value < 0.05.

Figure 2

NNT (upper row), ITAC (lower row). Stained tissue sections using antibodies against EIF2S1, EIF5A and EIF6 in tissue micro arrays (TMAs) at different resolutions.

Figure 3

Significant Wilcoxon p-values of the translation factors (p < 0.05) between the groups ITAC and NNT in TMA samples. Black bars and uppercase letters indicate that the arithmetic mean of the scores of the first group (ITAC) was higher than the arithmetic mean of the scores of the second group (NNT) and white bars and lowercase letters indicate the opposite. ** indicates a p-value < 0.01. The horizontal red line marks the threshold of 0.05.

Figure 4

Chi² p-values based on the scores for the proteins EIF2S1, EIF5A and EIF6 in combination with each subtype, location, stage and radiotherapy. Scores of 9 to 16 were considered as ‘yes’, scores of 0 and 8 as ‘no’. The horizontal line marks the threshold of 0.05.

Figure 5

Spearman correlations between groups and the translation factors EIF2S1, EIF5A and EIF6. The groups are based on clinical information. The scores of each eIF from the first group was correlated with the scores of the second group. For ‘RecMet gene upper-RecMet gene lower’ the recurrence time of the group with the higher scores was used (median split) and was correlated with the group with the lower scores for each eIF.

Figure 6

Kaplan–Meier diagrams of EIF2S1, EIF5A and EIF6 with scores of 1, 2, 3, 4 and 8 combined to ‘Lower’ and scores of 12 and 16 combined to ‘Higher’ based on time to recurrence/metastasis. The y-axis shows the survival probability, the x-axis the duration in months.