RT Journal Article
SR Electronic
T1 A Novel Nuclear Factor-κB Gene Signature Is Differentially Expressed in Head and Neck Squamous Cell Carcinomas in Association with TP53 Status
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 5680
OP 5691
DO 10.1158/1078-0432.CCR-07-0670
VO 13
IS 19
A1 Lee, Tin Lap
A1 Yang, Xin Ping
A1 Yan, Bin
A1 Friedman, Jay
A1 Duggal, Praveen
A1 Bagain, Lorena
A1 Dong, Gang
A1 Yeh, Ning T.
A1 Wang, Jie
A1 Zhou, Jian
A1 Elkahloun, Abdel
A1 Van Waes, Carter
A1 Chen, Zhong
YR 2007
UL http://clincancerres.aacrjournals.org/content/13/19/5680.abstract
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.