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NF‐κB and stat3 transcription factor signatures differentiate HPV ‐positive and HPV ‐negative head and neck squamous cell carcinoma
Author(s) -
Gaykalova Daria A.,
Manola Judith B.,
Ozawa Hiroyuki,
Zizkova Veronika,
Morton Kathryn,
Bishop Justin A.,
Sharma Rajni,
Zhang Chi,
Michailidi Christina,
Considine Michael,
Tan Marietta,
Fertig Elana J.,
Hennessey Patrick T.,
Ahn Julie,
Koch Wayne M.,
Westra William H.,
Khan Zubair,
Chung Christine H.,
Ochs Michael F.,
Califano Joseph A.
Publication year - 2015
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29558
Subject(s) - head and neck squamous cell carcinoma , cancer research , stat3 , biology , transcription factor , ap 1 transcription factor , gene , cancer , head and neck cancer , genetics
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.