International Journal of Clinical Case Reports 2024, Vol.14, No.5, 242-252 http://medscipublisher.com/index.php/ijccr 244 In China, a study on HPV18 genetic variability found that all detected variants belonged to lineage A, with no presence of lineages B or C. This study highlighted the predominance of sublineage A1 in the Taizhou region, Southeast China (Xu et al., 2018). In contrast, a study in Galicia, Spain, reported a higher prevalence of HPV16 lineage A and HPV18 lineage A, with lineage D of HPV16 being associated with an increased risk of high-grade cervical lesions and invasive cancer (Pérez et al., 2014). These findings underscore the importance of understanding the regional distribution of HPV variants to develop targeted screening and vaccination programs. The prevalence of specific variants can inform public health strategies and improve the effectiveness of interventions aimed at reducing the burden of cervical cancer. 3 Molecular Mechanisms of HPV16/18 Specific Variants in Oncogenesis Human papillomavirus (HPV) types 16 and 18 are the most common high-risk HPVs associated with cervical cancer. The oncogenic potential of these viruses is primarily attributed to the E6 and E7 oncoproteins, which interfere with various cellular processes to promote malignant transformation. 3.1 Effects of E6/E7 variants on cell cycle regulation The E6 and E7 oncoproteins of HPV16 and HPV18 play crucial roles in disrupting normal cell cycle regulation, a key step in oncogenesis. E7, in particular, is known to maintain cell cycle competence in differentiating keratinocytes by interacting with numerous host factors to manipulate gene expression patterns. E7 achieves this by binding to and degrading the retinoblastoma protein (pRb), thereby releasing E2F transcription factors that drive the expression of genes required for S-phase entry and DNA replication. This disruption of the pRb pathway leads to uncontrolled cell proliferation, a hallmark of cancer. Moreover, specific variants of E6 and E7 have been shown to have distinct effects on cell cycle regulation. For instance, the HPV16 Asian variant E6D25E exhibits unique proteomic patterns that correlate with enhanced cell transformation and suppression of the innate immune response (Chopjitt et al., 2016). This variant, like the prototype E6, degrades p53 and suppresses p21 induction, but it also modulates additional cellular proteins involved in cell cycle regulation and immune signaling, thereby contributing to its oncogenic potential. 3.2 Impact on DNA damage and repair pathways HPV16 and HPV18 oncoproteins also interfere with the host's DNA damage response (DDR) and repair mechanisms, further promoting genomic instability and cancer progression. The E6 and E7 proteins of HPV16 have been shown to globally hijack host DNA damage repair pathways, increasing cellular sensitivity to DNA repair inhibitors and enhancing the efficacy of radiotherapy. E6 and E7 interact with multiple DDR proteins, such as CHEK2, ERCC3, and XRCC6, altering their stability and subcellular localization, which compromises the host's ability to repair DNA damage effectively (Bruyère et al., 2023). Additionally, HPV16 E7 has been found to delay the repair of DNA damage by increasing the retention of γ-H2AX nuclear foci and decreasing sublethal DNA damage repair (Park et al., 2014). This delay is associated with the induction of Rad51, a protein involved in homologous recombination repair, suggesting that E7 manipulates DDR pathways to favor viral replication and persistence, ultimately contributing to oncogenesis. 3.3 Immune evasion mechanisms of HPV16/18 variants Immune evasion is another critical aspect of HPV16/18 oncogenesis. The E6 and E7 oncoproteins modulate host immune responses to create an environment conducive to viral persistence and tumor development. For example, the HPV16 Asian variant E6D25E has been shown to impair immune responses by targeting specific cellular proteins involved in TLR signaling and cell transformation (Chopjitt et al., 2016). This variant's ability to modulate the host proteome differently from the prototype E6 highlights the importance of specific viral variants in immune evasion. Furthermore, HPV16 E7 has been implicated in the regulation of immune-related genes. E7 can alter the expression of genes involved in immune regulation, growth factor signaling, and other pathways, thereby promoting immune evasion and persistence. These alterations in gene expression patterns help the virus evade
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