The Expression of HPV-16 E5 Oncoprotein Impacts the Transcript Profiles of FGFR2 and EMT-Related Genes in Preneoplastic Anal Epithelium Lesions

• Published in: International journal of molecular sciences 2024-11, Vol.25 (22), p.12085
• Main Authors: Raffa, Salvatore, Mancini, Vanessa, French, Deborah, Rollo, Francesca, Benevolo, Maria, Giuliani, Eugenia, Donà, Maria Gabriella, Ranieri, Danilo, Belleudi, Francesca
• Format: Article
• Language: English
• Subjects: Adult; Aged; Anal cancer; Anus Neoplasms - genetics; Anus Neoplasms - metabolism; Anus Neoplasms - pathology; Anus Neoplasms - virology; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Carcinoma, Squamous Cell - virology; Development and progression; DNA binding proteins; Epithelial-Mesenchymal Transition - genetics; Female; Fibroblast growth factors; Fibroblasts; Gene Expression Regulation, Neoplastic; Genes; Human papillomavirus; Human papillomavirus 16 - genetics; Humans; Hypotheses; Investigations; Male; Middle Aged; Oncogene Proteins, Viral - genetics; Oncogene Proteins, Viral - metabolism; Papillomavirus infections; Papillomavirus Infections - complications; Papillomavirus Infections - genetics; Papillomavirus Infections - pathology; Papillomavirus Infections - virology; Precancerous Conditions - genetics; Precancerous Conditions - metabolism; Precancerous Conditions - pathology; Precancerous Conditions - virology; Proteins; Receptor, Fibroblast Growth Factor, Type 2 - genetics; Receptor, Fibroblast Growth Factor, Type 2 - metabolism; Squamous cell carcinoma; Statistical analysis; Stem cells; Transcription factors; Transcriptome; Trends; Viroporin Proteins
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms252212085

Anal Squamous Cell Carcinoma (SCCA) is a rare Human Papillomavirus type 16 (HPV16)-associated carcinoma whose pathogenesis is still poorly understood. Recent studies based on biopsy and Next Generation Sequencing (NGS) approaches have linked the viral episomal status to aggressive SCCA phenotypes, suggesting a potential role of the 16E5 oncoprotein in tumor development. Our previous findings indicated that 16E5 induces Fibroblast Growth Factor Receptor 2 (FGFR2) isoform switching, aberrant mesenchymal FGFR2c expression, Epithelial Mesenchymal Transition (EMT), and cell invasion in various in vitro human keratinocyte models, as well as in the in vivo context of cervical Low-grade Squamous Intraepithelial Lesions (LSILs). To further explore the role of 16E5 in epithelial carcinogenesis, this study aims to investigate the molecular profile in HPV-related anal lesions. The results showed a significant positive correlation between 16E5 and FGFR2c, as well as 16E5 or FGFR2c and key EMT-related transcription factors, particularly in the group of HPV16 positive anal samples not containing without high grade lesions. Additionally, by coupling the molecular analysis with an interactome investigation, we hypothesized a potential functional interplay between the Ca channel Transient Receptor Potential Ankyrin 1 (TRPA1) and FGFR2c, mediated by 16E5 during the establishment of the oncogenic signaling. These findings will help to elucidate the actual relevance of 16E5 in the early progression of anal lesions and contribute to determine its potential as target for future preventive approaches for HPV16-positive SCCA.