title: Upregulation of nuclear factor-kappaB (NF-kappaB) is related to the grade of cervical intraepithelial neoplasia, but is not an independent predictor of high-risk human papillomavirus or disease outcome in cervical cancer.
abstract: Nuclear factor-kappaB (NF-kappaB) has a pivotal function in controlling a wide variety of gene functions, and has shown to be constitutively activated in many human cancers. The molecular links of NF-kappaB to oncogenic human papillomavirus (HPV) in cervical intraepithelial neoplasia (CIN) lesions and its prognostic value in cervical cancer (CC) are incompletely understood. As part of our HPV-PathogenISS study, a series of 150 squamous-cell carcinomas (SCCs) and 152 CIN lesions were examined using immunohistochemical staining for NF-kappaB, and tested for HPV using PCR with three primer sets (MY09/11, GP5+/GP6+, and SPF). Follow-up data were available from all SCC patients, and 67 CIN lesions had been monitored with serial PCR for HPV clearance/persistence after cone treatment. Cytoplasmic NF-kappaB expression was associated with CIN3/cancer at OR 3.55 (95% CI, 1.79-7.05), while nuclear NF-kappaB expression had an OR of 21.90 (95% CI, 2.96-161.74) (P = 0.0001). Strong nuclear expression was a rare event (8.8%) also in CC, but it was related to high-risk human papillomavirus (HR-HPV) detection, with OR 2.15 (95% CI, 1.08-4.30) (P = 0.022). This association was confounded, however, by the histological grade (Mantel-Haenszel common OR = 1.46; 95% CI, 0.70-3.03) (P = 0.308). Cytoplasmic or nuclear NF-kappaB expression did not predict clearance/persistence of HR-HPV after treatment of CIN, and neither one proved to be a prognostic predictor in CC. Overexpression of cytoplasmic NF-kappaB is significantly associated with progression to CIN3 and cancer. This is paralleled by only a slight increase in nuclear expression of NF-kappaB, which could be explained by the mechanisms whereby HR-HPVs escape from the transcriptional control of NF-kappaB, i.e., E7-mediated impaired nuclear translocation of cytoplasmic NF-kappaB, and E6-conditioned attenuated NF-kappaB (p65)-dependent transcriptional activity.
authors.affiliation: Unità Citoistopatologia, Centro Nazionale di Epidemiologia, Sorveglianza e Promozione della Salute, Istituto Superiore di Sanità (ISS), Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Branca
authors.forename: C
authors.initials: C
authors.lastname: Giorgi
authors.forename: M
authors.initials: M
authors.lastname: Ciotti
authors.forename: D
authors.initials: D
authors.lastname: Santini
authors.forename: L
authors.initials: L
authors.lastname: Di Bonito
authors.forename: S
authors.initials: S
authors.lastname: Costa
authors.forename: A
authors.initials: A
authors.lastname: Benedetto
authors.forename: D
authors.initials: D
authors.lastname: Bonifacio
authors.forename: P
authors.initials: P
authors.lastname: Di Bonito
authors.forename: P
authors.initials: P
authors.lastname: Paba
authors.forename: L
authors.initials: L
authors.lastname: Accardi
authors.forename: L
authors.initials: L
authors.lastname: Mariani
authors.forename: M
authors.initials: M
authors.lastname: Ruutu
authors.forename: S
authors.initials: S
authors.lastname: Syrjänen
authors.forename: C
authors.initials: C
authors.lastname: Favalli
authors.forename: K
authors.initials: K
authors.lastname: Syrjänen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D052685:Alphapapillomavirus / Q000235:genetics / Q000302:isolation & purification*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D005260:Female; D006801:Humans; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D009367:Neoplasm Staging; D030361:Papillomavirus Infections / Q000378:metabolism / Q000473:pathology*; D016133:Polymerase Chain Reaction; D018570:Risk Assessment; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D002578:Uterine Cervical Dysplasia / Q000378:metabolism* / Q000473:pathology / Q000821:virology*
chemical_list: D016328:NF-kappa B