NF-κB and stat3 transcription factor signatures differentiate HPV-positive and HPV-negative head and neck squamous cell carcinoma

Int J Cancer. 2015 Oct 15;137(8):1879-89. doi: 10.1002/ijc.29558. Epub 2015 Jun 23.


Using high-throughput analyses and the TRANSFAC database, we characterized TF signatures of head and neck squamous cell carcinoma (HNSCC) subgroups by inferential analysis of target gene expression, correcting for the effects of DNA methylation and copy number. Using this discovery pipeline, we determined that human papillomavirus-related (HPV+) and HPV- HNSCC differed significantly based on the activity levels of key TFs including AP1, STATs, NF-κB and p53. Immunohistochemical analysis confirmed that HPV- HNSCC is characterized by co-activated STAT3 and NF-κB pathways and functional studies demonstrate that this phenotype can be effectively targeted with combined anti-NF-κB and anti-STAT therapies. These discoveries correlate strongly with previous findings connecting STATs, NF-κB and AP1 in HNSCC. We identified five top-scoring pair biomarkers from STATs, NF-κB and AP1 pathways that distinguish HPV+ from HPV- HNSCC based on TF activity and validated these biomarkers on TCGA and on independent validation cohorts. We conclude that a novel approach to TF pathway analysis can provide insight into therapeutic targeting of patient subgroup for heterogeneous disease such as HNSCC.

Keywords: HNSCC; HPV; NF-κB; STAT3; transcription factor.

MeSH terms

  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / virology
  • Cell Line, Tumor
  • DNA Methylation
  • Gene Expression Regulation, Neoplastic
  • Head and Neck Neoplasms / genetics*
  • Head and Neck Neoplasms / metabolism
  • Head and Neck Neoplasms / virology
  • Humans
  • NF-kappa B / genetics*
  • NF-kappa B / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Papillomavirus Infections / genetics*
  • Papillomavirus Infections / metabolism
  • STAT3 Transcription Factor / genetics*
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Squamous Cell Carcinoma of Head and Neck


  • NF-kappa B
  • STAT3 Transcription Factor
  • STAT3 protein, human