HPV Enhances HNSCC Chemosensitization by Inhibiting SERPINB3 Expression to Disrupt the Fanconi Anemia Pathway

Area of Science:

• Oncology
• Molecular Biology
• Nanotechnology

Background:

• Head and neck squamous cell carcinoma (HNSCC) often shows poor prognosis due to chemotherapeutic resistance.
• Human papillomavirus (HPV)-positive HNSCC patients exhibit better chemosensitivity and prognosis than HPV-negative patients.
• The underlying mechanisms of HPV-mediated chemosensitivity to cisplatin are not fully understood.

Purpose of the Study:

• To identify the role of SERPINB3 in HPV-mediated cisplatin sensitivity in HNSCC.
• To elucidate the molecular mechanisms by which SERPINB3 influences DNA repair and chemosensitivity.
• To develop a targeted therapeutic strategy to overcome cisplatin resistance in HPV-negative HNSCC.

Main Methods:

• Identification of SERPINB3 as a target regulated by HPV-E6/E7.
• Investigating the effect of SERPINB3 downregulation on DNA damage repair pathways (Fanconi anemia pathway, USP1, FANCD2-FANCI).
• Utilizing pH-responsive nanoparticles for co-delivery of SERPINB3 small interfering RNA and cisplatin in patient-derived xenograft models.

Main Results:

• Downregulation of SERPINB3 inhibits cisplatin-induced DNA damage repair and enhances cytotoxicity.
• Reduced SERPINB3 expression interferes with USP1-mediated deubiquitination of FANCD2-FANCI, impairing DNA interstrand crosslink repair.
• Co-delivery of SERPINB3 siRNA and cisplatin using nanoparticles reversed cisplatin resistance in an HPV-negative HNSCC xenograft model.

Conclusions:

• SERPINB3 is a key mediator of cisplatin sensitivity regulated by HPV-E6/E7 in HNSCC.
• Targeting SERPINB3 offers a potential strategy to overcome cisplatin resistance in HPV-negative HNSCC.
• This approach may improve treatment outcomes and prognosis for HNSCC patients.