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A Novel Nuclear Factor-B Gene Signature Is Differentially Expressed in Head and Neck Squamous Cell Carcinomas in Association with TP53 Status

Authors' Affiliations: ¹ Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, ² Developmental Endocrinology Branch, National Institute of Child and Development, and ³ Microarray Unit, Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland

Requests for reprints: Zhong Chen or Carter Van Waes, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders/NIH, 10/5D55, MSC-1419, Bethesda, MD 20892-1419. Phone: 301-435-2073; Fax: 301-402-1140; E-mail: chenz{at}nidcd.nih.gov or vanwaesc{at}nidcd.nih.gov.

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-B (NF-B) 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-B signature, NF-B p65, and TP53 were examined in HNSCC tissue specimens by immunostaining. Predicted promoter binding and modulation of expression of candidate NF-B 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-B regulatory motifs. Coexpression of cluster B proteins was observed with strong NF-B phospho-p65 and weak TP53 staining, and NF-B phospho-p65 was inversely associated with TP53 (P = 0.02). Promoter binding of the NF-B signature genes was confirmed by p65 ChIP, and down-modulation of their expression and cell death were induced by p65 siRNA.

Conclusion: NF-B promotes expression of a novel NF-B–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.

Commentary

NF-B Gene Signatures and p53 Mutations in Head and Neck Squamous Cell Carcinoma

Robert L. Ferris and Jennifer R. Grandis
Clin. Cancer Res. 2007 13: 5663-5664. [Full Text] [PDF]

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