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. 2023 Dec 18;13:1273516. doi: 10.3389/fonc.2023.1273516

Figure 2.

Figure 2

Mechanisms of carcinogenesis induced by persistent HPV infections. Viral particles infect epithelial cells in the oral or oropharyngeal mucosa (A), with HPV DNA randomly integrating into the host cell genome (B). It is replicated as the epithelial cells multiply, and the virus is activated when it reaches the surface. After integration into the host cell genome, viral DNA is copied into mRNA, and proteins are released into the nucleus and cytoplasm. The E6 protein recruits the cellular ubiquitin-protein ligase E6AP and targets the cellular protein TP53 (C), which is involved in maintaining the genetic health of cells. Complexed with E6 and E6AP, TP53 protein is degraded in proteasomes (D), an event that promotes resistance to apoptosis and malignant progression. Lacking the DNA integrity checkpoint mechanism, the cell can accumulate defects, leading to genomic instability and malignant progression. On the other hand, the E6 protein, and less E7, forms a complex with E6AP and NEX1 (neurogenic differentiation factor 6) (E), which activates TERT/hTERT (F). This telomerase reverse transcriptase promotes telomere elongation and cell immortalization. Further, cells with inactive TP53 due to proteasomal degradation may acquire genetic instability and be transformed toward malignant progression. The E6 protein inactivates IFR3 (G), normally promoting the IFNA-IFNAR complex (H) formation. By inhibiting the formation of this complex, E6 decreases immune recognition of HPV and helps the spreading of HPV infection. The E5 protein activates the EGFR-mediated signaling pathway (I), promoting cell division and proliferation toward malignant progression. The E7 protein forms a complex with RB, leading to proteasome degradation (J). In the absence of RB, P16 synthesis is activated (K), which binds and disrupts CCND1 complexes with CDK4 and CDK6 (L), CCND1 contributing to uncontrolled DNA replication and cell division, which can further lead to malignant progression. The E7 protein stimulates CDK2 activity (M), leading to cell proliferation and malignant progression.