PT  - JOURNAL ARTICLE
AU  - Lee, Tin Lap
AU  - Yang, Xin Ping
AU  - Yan, Bin
AU  - Friedman, Jay
AU  - Duggal, Praveen
AU  - Bagain, Lorena
AU  - Dong, Gang
AU  - Yeh, Ning T.
AU  - Wang, Jie
AU  - Zhou, Jian
AU  - Elkahloun, Abdel
AU  - Van Waes, Carter
AU  - Chen, Zhong
TI  - A Novel Nuclear Factor-κB Gene Signature Is Differentially Expressed in Head and Neck Squamous Cell Carcinomas in Association with TP53 Status
AID  - 10.1158/1078-0432.CCR-07-0670
DP  - 2007 Oct 01
TA  - Clinical Cancer Research
PG  - 5680--5691
VI  - 13
IP  - 19
4099  - http://clincancerres.aacrjournals.org/content/13/19/5680.short
4100  - http://clincancerres.aacrjournals.org/content/13/19/5680.full
SO  - Clin Cancer Res2007 Oct 01; 13
AB  - Purpose: To determine if gene signatures differentially expressed in head and neck squamous cell carcinomas (HNSCC) are related to alterations in transcription factors nuclear factor-κB (NF-κB) and TP53 previously associated with decreased cell death, response to therapy, and worse prognosis. Experimental Design: Unique gene signatures expressed by HNSCC lines were identified by cDNA microarray, principal components, and cluster analyses and validated by quantitative reverse transcription-PCR (RT-PCR) and in situ hybridization. Bioinformatic analysis of the promoters and ontogeny of these clustered genes was done. Expression of proteins encoded by genes of a putative NF-κB signature, NF-κB p65, and TP53 were examined in HNSCC tissue specimens by immunostaining. Predicted promoter binding and modulation of expression of candidate NF-κB genes and cell survival were evaluated by p65 chromatin immunoprecipitation (ChIP) and small interfering RNA (siRNA) knockdown. Results: Two groups of HNSCC exhibiting distinct gene signatures were identified: cluster A enriched for histone genes, with a higher prevalence of TP53 promoter binding motifs; and cluster B enriched for injury response genes with NF-κB regulatory motifs. Coexpression of cluster B proteins was observed with strong NF-κB phospho-p65 and weak TP53 staining, and NF-κB phospho-p65 was inversely associated with TP53 (P = 0.02). Promoter binding of the NF-κB signature genes was confirmed by p65 ChIP, and down-modulation of their expression and cell death were induced by p65 siRNA. Conclusion: NF-κB promotes expression of a novel NF-κB–related gene signature and cell survival in HNSCC that weakly express TP53, a subset previously associated with inactivated wild-type TP53, greater resistance to chemoradiotherapy, and worse prognosis.