Yan Bin, Chen Guang, Saigal Kunal, Yang Xinping, Jensen Shane T, Van Waes Carter, Stoeckert Christian J, Chen Zhong
Head and Neck Surgery Branch, NIDCD, National Institutes of Health, Bethesda, MD 20892, USA.
Genome Biol. 2008;9(3):R53. doi: 10.1186/gb-2008-9-3-r53. Epub 2008 Mar 11.
Aberrant activation of the nuclear factor kappaB (NF-kappaB) pathway has been previously implicated as a crucial signal promoting tumorigenesis. However, how NF-kappaB acts as a key regulatory node to modulate global gene expression, and contributes to the malignant heterogeneity of head and neck cancer, is not well understood.
To address this question, we used a newly developed computational strategy, COGRIM (Clustering Of Gene Regulons using Integrated Modeling), to identify NF-kappaB regulons (a set of genes under regulation of the same transcription factor) for 1,265 genes differentially expressed by head and neck cancer cell lines differing in p53 status. There were 748 NF-kappaB targets predicted and individually annotated for RELA, NFkappaB1 or cREL regulation, and a prevalence of RELA related genes was observed in over-expressed clusters in a tumor subset. Using Ingenuity Pathway Analysis, the NF-kappaB targets were reverse-engineered into annotated signature networks and pathways, revealing relationships broadly altered in cancer lines (activated proinflammatory and down-regulated Wnt/beta-catenin and transforming growth factor-beta pathways), or specifically defective in cancer subsets (growth factors, cytokines, integrins, receptors and intermediate kinases). Representatives of predicted NF-kappaB target genes were experimentally validated through modulation by tumor necrosis factor-alpha or small interfering RNA for RELA or NFkappaB1.
NF-kappaB globally regulates diverse gene programs that are organized in signal networks and pathways differing in cancer subsets with distinct p53 status. The concerted alterations in gene expression patterns reflect cross-talk among NF-kappaB and other pathways, which may provide a basis for molecular classifications and targeted therapeutics for heterogeneous subsets of head and neck or other cancers.
核因子κB（NF-κB）信号通路的异常激活先前已被认为是促进肿瘤发生的关键信号。然而，NF-κB如何作为关键调节节点来调控整体基因表达，并导致头颈癌的恶性异质性，目前尚不清楚。
为了解决这个问题，我们使用了一种新开发的计算策略COGRIM（使用综合建模的基因调控簇分析），来识别1265个在p53状态不同的头颈癌细胞系中差异表达的基因的NF-κB调控簇（受同一转录因子调控的一组基因）。预测出748个NF-κB靶标，并分别注释了RELA、NFκB1或cREL调控，且在肿瘤亚群的过表达簇中观察到RELA相关基因的优势。利用 Ingenuity 通路分析，将NF-κB靶标反向工程到注释的特征网络和通路中，揭示了在癌细胞系中广泛改变的关系（促炎激活以及Wnt/β-连环蛋白和转化生长因子-β通路下调），或在癌症亚群中特异性缺陷的关系（生长因子、细胞因子、整合素、受体和中间激酶）。通过肿瘤坏死因子-α或针对RELA或NFκB1的小干扰RNA进行调控，对预测的NF-κB靶标基因的代表性基因进行了实验验证。
NF-κB全局调控不同的基因程序，这些程序组织在具有不同p53状态的癌症亚群的信号网络和通路中。基因表达模式的协同改变反映了NF-κB与其他通路之间的相互作用，这可能为头颈癌或其他癌症的异质性亚群的分子分类和靶向治疗提供基础。
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