Why HPV16? Why, now, HPV42? How the discovery of HPV42 in rare cancers provides an opportunity to challenge our understanding about the transition between health and disease for common members of the healthy microbiota.

In 2022, a bioinformatic, agnostic approach identified HPV42 as causative agent of a rare cancer, later confirmed experimentally. This unexpected association offers an opportunity to reconsider our understanding about papillomavirus infections and cancers. We have expanded our knowledge about the diversity of papillomaviruses and the diseases they cause.

The exon junction complex core factor eIF4A3 is a key regulator of HPV16 gene expression.

High-risk human papillomavirus (hrHPVs), particularly HPV16 and HPV18, are the etiologic factors of ano-genital cancers and some head and neck squamous cell carcinomas (HNSCCs). Viral E6 and E7 oncoproteins, controlled at both transcriptional and post-transcriptional levels, drive hrHPVs-induced carcinogenesis. In the present study, we investigated the implication of the DEAD-box helicase eukaryotic translation initiation factor 4A3 (eIF4A3,) an Exon Junction Complex factor, in the regulation of HPV16 gene expression.

DNA demethylation agent 5azadC downregulates HPV16 E6 expression in cervical cancer cell lines independently of TBX2 expression.

HPV16 is the most carcinogenic human papillomavirus and causes >50% of cervical cancers, the majority of anal cancers and 30% of oropharyngeal squamous cell carcinomas. HPV carcinogenesis relies on the continuous expression of the two main viral oncoproteins E6 and E7 that target >150 cellular proteins. Among them, epigenetic modifiers, including DNA Methyl Transferases (DNMT), are dysregulated, promoting an aberrant methylation pattern in HPV-positive cancer cells.

Comparative RNA sequencing reveals that HPV16 E6 abrogates the effect of E6*I on ROS metabolism.

High-risk Human Papillomavirus infections are responsible for anogenital and oropharyngeal cancers. Alternative splicing is an important mechanism controlling HPV16 gene expression. Modulation in the splice pattern leads to polycistronic HPV16 early transcripts encoding a full length E6 oncoprotein or truncated E6 proteins, commonly named E6*.