Upregulation of Nuclear Factor-κB (NF-κB) 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

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Abstract

Nuclear factor-κB (NF-κB) 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-κB 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-κB, 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-κB expression was associated with CIN3/cancer at OR 3.55 (95% CI, 1.79-7.05), while nuclear NF-κB 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 (HRHPV) 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-κB 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-κB is significantly associated with progression to CIN3 and cancer. This is paralleled by only a slight increase in nuclear expression of NF-κB, which could be explained by the mechanisms whereby HR-HPVs escape from the transcriptional control of NF-κB, i.e., E7-mediated impaired nuclear translocation of cytoplasmic NF-κB, and E6-conditioned attenuated NF-κB (p65)-dependent transcriptional activity.

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