On the Regulation of NF-κB Pathway by HPV Oncoproteins: Are Pathway Inhibitors a Good Alternative for the Treatment of Cervical Cancer?

Cervical cancer (CC) is one of the most prevalent cancer-related pathologies in the female population. It is considered the second leading cause of cancer-related deaths in developing countries. The most important etiological factor for the development of CC is the persistent infection with high-risk human papillomavirus. HPV-oncoproteins have evolved to modulate cellular mechanisms to permit viral replication and the generation of new infectious viral particles. When the viral infection persists, there is an uncontrolled viral protein expression essential to commence and maintain the transformation of infected cells. Different cell pathways are affected during the transformation stage, including the NF-κB signaling pathway. NF-κB controls different cellular mechanisms, and its role is critical for various processes, such as immunity, inflammation, cell differentiation, growth, and survival. NF-κB plays a double role in the development of CC. Evidence suggests that in the early stages of viral infection, the NF-κB activity impairs viral transcription and is beneficial for avoiding cellular immortalization. However, in the advanced stages of cervical carcinogenesis, the activation of the NF-κB correlates with a poor prognosis. Here, we discuss some aspects of NF-κB activity during the development of CC and the use of NF-κB inhibitors to treat this pathology.

FOXP3 Isoforms Expression in Cervical Cancer: Evidence about the Cancer-Related Properties of FOXP3Δ2Δ7 in Keratinocytes.

Cervical cancer (CC) is the fourth most common type of cancer among women; the main predisposing factor is persistent infection by high-risk human papillomavirus (hr-HPV), mainly the 16 or 18 genotypes. Both hr-HPVs are known to manipulate the cellular machinery and the immune system to favor cell transformation. FOXP3, a critical transcription factor involved in the biology of regulatory T cells, has been detected as highly expressed in the tumor cells of CC patients. However, its biological role in CC, particularly in the keratinocytes, remained unclarified. Therefore, this work aimed to uncover the effect of FOXP3 on the biology of the tumoral cells. First, public databases were analyzed to identify the FOXP3 expression levels and the transcribed isoforms in CC and normal tissue samples. The study's findings demonstrated an increased expression of FOXP3 in HPV16+ CC samples. Additionally, the FOXP3Δ2 variant was detected as the most frequent splicing isoform in tumoral cells, with a high differential expression level in metastatic samples. However, the analysis of FOXP3 expression in different CC cell lines, HPV+ and HPV-, suggests no relationship between the presence of HPV and FOXP3 expression. Since the variant FOXP3Δ2Δ7 was found highly expressed in the HPV16+ SiHa cell line, a model with constitutive expression of FOXP3Δ2Δ7 was established to evaluate its role in proliferation, migration, and cell division. Finally, RNAseq was performed to identify differentially expressed genes and enriched pathways modulated by FOXP3Δ2Δ7. The exogenous expression of FOXP3Δ2Δ7 promotes cell division, proliferation, and migration. The transcriptomic analyses highlight the upregulation of multiple genes with protumor activities. Moreover, immunological and oncogenic pathways were detected as highly enriched. These data support the hypothesis that FOXP3Δ2Δ7 in epithelial cells induces cancer-related hallmarks and provides information about the molecular events triggered by this isoform, which could be important for developing CC.