NF-κB Activation Is Essential for Cervical Cell Proliferation and Malignant Transformation

NF-κB, a multifunctional transcription factor, is linked to cancer initiation and progression. As a key immune mediator, it may play a crucial role in HPV-induced cervical carcinogenesis. However, consensus is lacking on the activation timing of NF-κB during the transition from cervical intraepithelial neoplasia (CIN) to cervical squamous cell carcinoma (CSCC). In this study, immunohistochemical analysis was performed to examine RELA, one of the important members of the NF-κB family, and phospho-RELA expression in different cervical lesions. Then, we analyzed NF-κB regulation of differentially expressed genes (DEGs) in cervical lesions vs. normal tissues. Gene enrichment identified oncogenic DEGs, followed by expression and survival analyses. The impact of NF-κB activation on cervical cell proliferation, migration, and oncogenic regulation, as well as the effects of inhibiting NF-κB, were examined. Our study showed that NF-κB activation starts in cervical simple hyperplasia and intensifies as CIN evolves to CSCC. NF-κB-regulated DEGs show stage-specific functions: immune regulation in CIN and cancer promotion in CSCC. Short-term NF-κB activation boosts cervical cell proliferation and migration, which is reversible by an NF-κB inhibitor. Long-term NF-κB activation promotes the expression of cancer-promoting genes in normal cells and also maintains them in cancer tissues, which is linked to poorer prognosis. Inhibiting NF-κB downregulates these genes in cancer cells and suppresses the oncogenic abilities of cervical cancer cells. Collectively, NF-κB activation initiates during the simple hyperplasia stage of cervical cells, stimulating proliferation, migration, and oncogene expression. Throughout the transition from CIN to CSCC, NF-κB activation progressively intensifies, and its long-term activation promotes carcinogenesis. Thus, NF-κB is crucial in mediating cervical oncogenic transformation.