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NRF2 Activation in Trp53;p16-deficient Mice Drives Oral Squamous Cell Carcinoma

Samera H Hamad1,2,3, Rani S Sellers1,4, Nathan Wamsley5

  • 1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina.

Cancer Research Communications
|February 9, 2024
PubMed

Insights

Constitutive activation of the NRF2 (NFE2L2) transcription factor drives oral cavity squamous cell carcinoma (OSCC) in mice lacking p53 and p16 tumor suppressors. This new model mimics human HNSCC genetics, aiding OSCC research.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Aberrant activation of the NRF2 (Nuclear factor erythroid 2-related factor 2) transcription factor is common in head and neck squamous cell carcinomas (HNSCC).
  • NRF2 activation alone does not cause cancer but promotes tumor initiation and progression when combined with oncogenes.
  • Loss of tumor suppressor genes p16INK4A and p53 is frequently observed in human HNSCC.

Purpose of the Study:

  • To investigate the oncogenic role of NRF2 in the context of p16 and p53 loss in HNSCC.
  • To develop a novel, human-relevant mouse model for oral cavity squamous cell carcinoma (OSCC).

Main Methods:

  • Deletion of p16INK4A and p53 tumor suppressor genes in mice (CP mice).
  • Introduction of a constitutively active NRF2E79Q mutant in CP mice (CPN mice).
  • Histopathological analysis of tumor development in the esophagus, oropharynx, forestomach, and oral cavity.

Main Results:

  • CPN mice developed squamous cell hyperplasia, dysplasia, and OSCC in the oral cavity.
  • CP mice with wild-type NRF2 did not develop oral cavity lesions.
  • Both CP and CPN mice developed abdominal sarcomas and carcinomas.
  • NRF2 activation drives OSCC in the context of p53 and p16 loss.

Conclusions:

  • NRF2 acts as an oncogene in driving OSCC when p53 and p16 tumor suppressors are lost.
  • CPN mice provide a new, genetically relevant model for studying OSCC initiation, progression, and therapeutic response.

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