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

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    Date
    2015
    Author
    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.
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    Abstract
    Abstract
    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.
    Citation:
    Gaykalova, D. A., Manola, J. B., Ozawa, H. , Zizkova, V. , Morton, K. , Bishop, J. A., Sharma, R. , Zhang, C. , Michailidi, C. , Considine, M. , Tan, M. , Fertig, E. J., Hennessey, P. T., Ahn, J. , Koch, W. M., Westra, W. H., Khan, Z. , Chung, C. H., Ochs, M. F. and Califano, J. A. (2015), NF‐κB and stat3 transcription factor signatures differentiate HPV‐positive and HPV‐negative head and neck squamous cell carcinoma. Int. J. Cancer, 137: 1879-1889.
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    URI
    https://dx.doi.org/10.1002/ijc.29558
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