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Human Papilloma Virus Does Not Fully Inactivate p53 Cellular Activity in HNSCC

Jovanka Gencel-Augusto1,2, Hua Li1,2, Liam C Woerner1,2

  • 1Department of Otolaryngology-Head and Neck Surgery, University of California San Francisco (UCSF), San Francisco, California, USA.

Head & Neck
|October 31, 2025
PubMed

Insights

Head and neck squamous cell carcinoma (HNSCC) with wild-type TP53 and human papillomavirus (HPV+) shows residual p53 activity, improving patient survival. Loss of this p53 function in HPV+ HNSCC promotes tumor growth and suggests new therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Head and neck squamous cell carcinoma (HNSCC) is a significant global health concern.
  • Tumor suppressor p53 inactivation is a frequent event in HNSCC, occurring via TP53 mutations or human papillomavirus (HPV)-mediated degradation.
  • HPV-positive (HPV+) HNSCC generally has better outcomes than HPV-negative HNSCC, but a subset of HPV+ tumors harbor TP53 mutations.

Purpose of the Study:

  • To investigate the role and extent of p53 activity in HPV+ HNSCC, particularly in tumors with wild-type (WT) TP53.
  • To explore the functional consequences of p53 loss in HPV+ HNSCC.
  • To identify potential therapeutic vulnerabilities associated with p53 status in HPV+ HNSCC.

Main Methods:

  • Analysis of clinical outcomes based on HPV and TP53 mutation status.
  • In vitro experiments assessing proliferation, migration, and invasion of HPV+ HNSCC cells with varying p53 status.
  • Transcriptomic analysis to identify p53-dependent gene regulation.
  • Assessment of genomic alterations and signaling pathway activity (e.g., PI3K-AKT).

Main Results:

  • HPV+ TP53-WT HNSCC cells exhibit residual tumor suppressive p53 activity.
  • Patients with HPV+ TP53-WT tumors show significantly better survival compared to those with HPV+ TP53-mutant or HPV-negative tumors.
  • Loss of WT p53 in HPV+ HNSCC enhances tumor cell proliferation, migration, and invasion, alters methylation patterns, increases chromosomal instability, and impacts PI3K-AKT signaling.

Conclusions:

  • p53 is not completely inactivated in all HPV+ HNSCC, with residual tumor suppressive functions present in WT cases.
  • p53 loss in HPV+ HNSCC contributes to aggressive tumor behavior and altered signaling pathways, including PI3K-AKT.
  • TP53 status may be a valuable biomarker for stratifying HPV+ HNSCC patients and identifying novel therapeutic targets, such as PI3K pathway inhibition.
Keywords:
HNSCCHPVPI3Kp53tumor suppression

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