mTOR downstream effectors, 4EBP1 and eIF4E, are overexpressed and associated with HPV status in precancerous lesions and carcinomas of the uterine cervix

Abstract

The present study aims to investigate the expression levels of two critical mammalian target of rapamycin (mTOR) downstream effectors, 4E binding protein 1 (4EBP1) and eukaryotic initiation factor 4E (eIF4E) proteins, in precancerous squamous intraepithelial lesions and cancer of the uterine cervix, and their association with human papilloma virus (HPV) infection status. Uterine cervical biopsies from 73 patients were obtained, including 40 fresh-frozen samples and 42 archival formalin-fixed, paraffin-embedded tissue specimens. Whole protein extracts were analyzed for the expression of 4EBP1 and eIF4E proteins using western blotting. In addition, distribution of 4EBP1 and eIF4E protein expression and 4EBP1 phosphorylation (P-4EBP1) were analyzed by immunohistochemistry in archival tissues and correlated with the degree of dysplasia. The presence of high-risk HPV (HR-HPV) types was assessed by polymerase chain reaction. Using western blot analysis, high expression levels of 4EBP1 and eIF4E were observed in all uterine cervical carcinomas, which significantly correlated with the degree of dysplasia. By immunohistochemistry, overexpression of 4EBP1 and eIF4E was detected in 20 of 21 (95%) and 17 of 21 (81%) samples, respectively, in patients with high-grade dysplasia and carcinomas, compared with 1 of 20 (5%) and 2 of 20 (10%) samples, respectively, in patients with low-grade lesions or normal histology. All 4EBP1-positive cases tested were also positive for P-4EBP1. Furthermore, overexpression of 4EBP1 and eIF4E significantly correlated with the presence of HR-HPV oncogenic types. The present study demonstrated that critical effectors of mTOR signaling, which control protein synthesis initiation, are overexpressed in cervical high-grade dysplasia and cancer, and their levels correlate with oncogenic HPV types. These findings may provide novel targets for investigational therapeutic approaches in patients with cancer of the uterine cervix.

Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

“…Housekeeping mRNAs, for example, cytoskeleton proteins, require a low level of eIF4E, whereas proto-oncogenic and prosurvival proteins such as c-Myc, cyclin D1, Pim-1, survivin, Bcl-2, VEGF have a much higher dependency on eIF4E for translation [11,12]. These mRNAs are termed as 'weak mRNAs' and are greatly influenced by an increase in eIF4E levels, observed in 30% of human cancers [13][14][15]. The availability of eIF4E is regulated by 4E-binding proteins, which compete with eIF4G for a common surface to bind to eIF4E [4,16,17].…”

The high‐risk HPV E6 proteins modify the activity of the eIF4E protein via the MEK/ERK and AKT/PKB pathways

“…Previous studies have suggested that the aberrant activation of the eIF4F complex is implicated in the initiation and promotion of cervical carcinogenesis-mediated by HPV. Although the relationship between HPV infection and activation of the eIF4F complex is not completely understood, histopathological evidence indicates the involvement of eIF4E alteration in the progression of cervical cancer [13,14]. In this study, we investigated the mechanisms through which E6 proteins of low-risk (6E6) and high-risk (16E6, 18E6, and 52E6) genotypes can modify the activity of the eIF4E protein and their possible effects on the downstream targets of the eIF4F complex, CCND1, and ODC1.…”

“…Previous studies have suggested that the increased levels of eIF4E during cervical carcinogenesis cause an increase in the rate of synthesis of the early oncoproteins of high-risk HPV (HR-HPV) [14,25]. This finding is related to the indirect effect of E6 oncoproteins on the transcriptional activation of the eIF4E promoter via the stimulation of p53 degradation.…”

“…The expression of the eIF4E protein is frequently altered in a wide variety of benign and malignant hyperproliferative disorders, including cancer [10][11][12]. Previous studies found that the expression of the eIF4E protein increases relative to the severity of cervical malignancy [13][14][15]. However, although epidemiological evidence regarding the causal relationship between HPV infection and eIF4E is scarce, the overexpression and phosphorylation of eIF4E (Serine-209) have been associated with high-risk HPV genotype infection [14].…”

Cervical cancer metastasis to the brain: A case report and review of literature

“…Additionally, signaling activation of the protein kinase mTOR, which is involved in protein synthesis, has been noted in both HPV-negative and HPV-positive cervical cancer tissues and cell lines; mTOR inhibitors have also shown to effectively decrease the activity of mTOR along with remarkably decreasing tumor burden. [ 4 ] Li et al . [ 30 ] also identified increased levels of the oncoprotein HBXIP in patients with squamous cell carcinoma of the cervix compared to normal cervical epithelial and that high expression of this protein was related to invasive and metastatic disease with overall lower survival rates.…”