Human Papillomavirus Pathogenesis in Cervical Cancer

Human Papillomavirus (HPV) is responsible for the vast majority of cervical cancers through a series of well-characterised molecular events that begin with infection of the basal epithelium and can culminate in invasive malignancy. High-risk HPV types, notably HPV16 and HPV18, establish persistent infection by replicating as episomal genomes in dividing keratinocytes, evading immune detection and activating key oncoproteins E6 and E7. These oncoproteins subvert tumour suppressor pathways—E6 targeting p53 for degradation and E7 binding retinoblastoma protein—thereby promoting cell cycle progression, genomic instability and evasion of apoptosis. Over time, viral DNA can integrate into the host genome, disrupting cellular homeostasis and amplifying oncogenic potential. Integration events foster copy number alterations, chromosomal rearrangements and activation of telomerase, driving clonal evolution and intratumoral heterogeneity. Cervical neoplastic lesions are graded by histopathology, reflecting accumulation of genetic and epigenetic alterations and heralding progression from cervical intraepithelial neoplasia to invasive carcinoma. Vaccination programmes targeting HPV L1 capsid proteins and enhanced screening through molecular assays have reduced incidence, yet challenges remain in understanding mechanisms of persistence, immune evasion and progression to malignancy on a global scale. A deeper knowledge of virus–host interactions at both the molecular and tissue level is crucial for the development of next-generation therapeutics and effective public health strategies.

Research from Nature Portfolio

Recent structural biology efforts have elucidated the atomic details of the complex formed by HPV16 E6, the cellular ubiquitin ligase E6AP and the tumour suppressor p53 using single-particle cryo-electron microscopy. This high-resolution structure reveals extensive interfaces that underpin the picomolar affinity of the ternary complex, explaining prior challenges in disrupting this interaction therapeutically and suggesting new avenues for targeted drug design. Complementing this, large-scale genomic analyses across multiple cancer types have mapped the landscape of viral integration, showing that HPV integration is associated with local copy number changes, mutual exclusivity with key driver mutations and the emergence of APOBEC mutational signatures. Integration events at sites such as the TERT promoter correlate with elevated telomerase expression, implicating this mechanism in tumour maintenance and highlighting potential biomarkers for patient stratification.

Human Papillomavirus Pathogenesis in Cervical Cancer publication trend

The graph below shows the total number of articles in human papillomavirus pathogenesis in cervical cancer across all publications each year (not limited to Nature Index journals).

Technical terms

Oncoprotein: A viral or cellular protein whose expression contributes to the initiation and maintenance of cancer.

Episome: A circular DNA molecule maintained independently of host chromosomes in dividing cells.

Integration: The insertion of viral DNA into the host genome, often resulting in genomic instability.

Heterocateny: A structural variation in which interrelated tandem repeats of viral and host DNA form complex concatemers.

APOBEC mutational signature: A pattern of cytosine deamination-driven mutations associated with APOBEC enzyme activity.

Cryo-electron microscopy: A technique for determining high-resolution three-dimensional structures of proteins and complexes at cryogenic temperatures.

References

1. Intratumoral heterogeneity and clonal evolution induced by HPV integration. Cancer Discovery (2023).
2. Structure of the p53 degradation complex from HPV16. Nature Communications (2024).
3. The landscape of viral associations in human cancers. Nature Genetics (2020).
4. Human Papillomavirus E6 and E7: The Cervical Cancer Hallmarks and Targets for Therapy. Frontiers in Microbiology (2020).
5. The role of the PI3K/Akt/mTOR signalling pathway in human cancers induced by infection with human papillomaviruses. Molecular Cancer (2015).
6. The human papillomavirus replication cycle, and its links to cancer progression: a comprehensive review.. Clinical Science (2017).
7. The role of integration in oncogenic progression of HPV-associated cancers. PLOS Pathogens (2017).
8. High-Risk Human Papillomaviral Oncogenes E6 and E7 Target Key Cellular Pathways to Achieve Oncogenesis. International Journal of Molecular Sciences (2018).