HPV16 E2 enhances the expression of NF-κB and STAT3 target genes and potentiates NF-κB activation by inflammatory mediators

• Cervicitis tissues with HPV16 E2 exhibit high levels of NF-κB/STAT3 target genes.
• Expression analysis of NF-κB-STAT3 target proteins indicates their early activation.
• Cervicitis tissues with HPV16 E2 exhibit elevated expression of Pin1.
• E2 potentiates NF-κB activation induced by inflammatory mediators in HEK293 cells.

HPV-transformed cells exhibit activation of NF-κB and STAT3 (mediators of inflammation), but very little is known about their regulation under inflammatory conditions before HPV integration. This study reports that cervical tissues with stromal inflammation and intact HPV16 E2 gene show increased expression of target genes of NF-κB and/or STAT3 which can regulate cell survival (cyclin D1, c-Myc, survivin and Bcl2) and inflammatory responses (TNF-α, IL-1β, IL-6, IL-8 and CCR2). Increased expression of RelA, p-IκBα, STAT3, p-STAT3 (Ser727), Pin1 (peptidyl-prolyl cis/trans isomerase) and MCM2 in the squamous epithelia of cervices with stromal inflammation supports early activation of NF-κB-STAT3. Furthermore, HPV16 E2 potentiated NF-κB activation induced by inflammatory mediators, IL-1β and SDF-1α, in HEK293 cells. These results reveal a novel role for E2 in regulating the activities of NF-κB and STAT3 that may have implications in carcinogenic progression of HPV16-infected cells under conditions of stromal inflammation.