title: 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.
authors.affiliation: First Department of Pathology, National and Kapodistrian University of Athens, School of Medicine, GR-11527 Athens, Greece.
authors.forename: Aristidis
authors.initials: A
authors.lastname: Asimomytis
authors.affiliation: First Department of Pathology, National and Kapodistrian University of Athens, School of Medicine, GR-11527 Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Karanikou
authors.affiliation: First Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Alexandra Maternity Hospital, GR-11528 Athens, Greece.
authors.forename: Alexander
authors.initials: A
authors.lastname: Rodolakis
authors.affiliation: First Department of Pathology, National and Kapodistrian University of Athens, School of Medicine, GR-11527 Athens, Greece.
authors.forename: Anna
authors.initials: A
authors.lastname: Vaiopoulou
authors.affiliation: First Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Alexandra Maternity Hospital, GR-11528 Athens, Greece.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Tsetsa
authors.affiliation: Second Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Aretaieion Hospital, GR-11528 Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Creatsas
authors.affiliation: Department of Obstetrics and Gynecology, University of Ioannina, School of Medicine, GR-45110 Ioannina, Greece.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Stefos
authors.affiliation: First Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Alexandra Maternity Hospital, GR-11528 Athens, Greece.
authors.forename: Aristidis
authors.initials: A
authors.lastname: Antsaklis
authors.affiliation: First Department of Pathology, National and Kapodistrian University of Athens, School of Medicine, GR-11527 Athens, Greece.
authors.forename: Efstratios
authors.initials: E
authors.lastname: Patsouris
authors.affiliation: First Department of Pathology, National and Kapodistrian University of Athens, School of Medicine, GR-11527 Athens, Greece; Department of Pathology and Cytology, Karolinska University Hospital and Karolinska Institute, Solna 17176, Sweden.
authors.forename: George Z
authors.initials: GZ
authors.lastname: Rassidakis
keywords: 4EBP1; Ca; HG-SIL; HPV; LG-SIL; eIF4E