NF-κB and stat3 transcription factor signatures differentiate HPV-positive and HPV-negative head and neck squamous cell carcinoma.
NF-κB and stat3 transcription factor signatures differentiate HPV-positive and HPV-negative head and neck squamous cell carcinoma.
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DOI：
10.1002/ijc.29558
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发表时间：
2015-10-15
影响因子：
6.4
通讯作者：
Califano JA
中科院分区：
文献类型：
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作者：
Gaykalova DA;Manola JB;Ozawa H;Zizkova V;Morton K;Bishop JA;Sharma R;Zhang C;Michailidi C;Considine M;Tan M;Fertig EJ;Hennessey PT;Ahn J;Koch WM;Westra WH;Khan Z;Chung CH;Ochs MF;Califano JA
利用高通量分析和TRANSFAC数据库，我们通过对靶基因表达的推断分析，校正了DNA甲基化和拷贝数的影响，表征了头颈部鳞状细胞癌（HNSCC）亚群的TF特征。利用这一发现管道，我们确定人乳头瘤病毒相关（HPV+）和HPV - HNSCC在关键tf（包括AP1、STATs、NF-κB和p53）的活性水平上存在显著差异。免疫组织化学分析证实，HPV - HNSCC具有STAT3和NF-κB信号通路共同激活的特征，功能研究表明，联合抗NF-κB和抗stat治疗可以有效靶向这种表型。这些发现与先前在HNSCC中发现的STATs、NF-κB和AP1密切相关。我们从STATs、NF-κB和AP1途径中鉴定出5对得分最高的生物标志物，这些生物标志物基于TF活性区分HPV+和HPV - HNSCC，并在TCGA和独立验证队列上验证了这些生物标志物。我们的结论是，一种新的TF通路分析方法可以为异质性疾病（如HNSCC）的患者亚组治疗靶向提供见解。
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 5 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.