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Systems biology-defined NF-kappaB regulons, interacting signal pathways and networks are implicated in the malignant phenotype of head and neck cancer cell lines differing in p53 status.

ABSTRACT: BACKGROUND: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. RESULTS: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. CONCLUSION: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.

SUBMITTER: Yan B

PROVIDER: S-EPMC2397505 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Systems biology-defined NF-kappaB regulons, interacting signal pathways and networks are implicated in the malignant phenotype of head and neck cancer cell lines differing in p53 status.

Yan Bin B Chen Guang G Saigal Kunal K Yang Xinping X Jensen Shane T ST Van Waes Carter C Stoeckert Christian J CJ Chen Zhong Z

Genome biology 20080311 3

<h4>Background</h4>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.<h4>Results</h4>To address this question, we used a newly developed computational strategy, COGRIM (Clustering Of Gene Regulons using Integrated Modelin ...[more]

PMID: 18334025

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Project description:Glioblastoma multiforme (GBM) is characterized by rapid growth, invasion and resistance to chemo-/radiotherapy. The complex cell surface morphology with abundant membrane folds, microvilli, filopodia and other membrane extensions is believed to contribute to the highly invasive behavior and therapy resistance of GBM cells. The present study addresses the mechanisms leading to the excessive cell membrane area in five GBM lines differing in mutational status for PTEN and p53. In addition to scanning electron microscopy (SEM), the membrane area and folding were quantified by dielectric measurements of membrane capacitance using the single-cell electrorotation (ROT) technique. The osmotic stability and volume regulation of GBM cells were analyzed by video microscopy. The expression of PTEN, p53, mTOR and several other marker proteins involved in cell growth and membrane synthesis were examined by Western blotting. The combined SEM, ROT and osmotic data provided independent lines of evidence for a large variability in membrane area and folding among tested GBM lines. Thus, DK-MG cells (wild type p53 and wild type PTEN) exhibited the lowest degree of membrane folding, probed by the area-specific capacitance C m?=?1.9 µF/cm(2). In contrast, cell lines carrying mutations in both p53 and PTEN (U373-MG and SNB19) showed the highest C m values of 3.7-4.0 µF/cm(2), which corroborate well with their heavily villated cell surface revealed by SEM. Since PTEN and p53 are well-known inhibitors of mTOR, the increased membrane area/folding in mutant GBM lines may be related to the enhanced protein and lipid synthesis due to a deregulation of the mTOR-dependent downstream signaling pathway. Given that membrane folds and extensions are implicated in tumor cell motility and metastasis, the dielectric approach presented here provides a rapid and simple tool for screening the biophysical cell properties in studies on targeting chemo- or radiotherapeutically the migration and invasion of GBM and other tumor types.

Dataset Information

Systems biology-defined NF-kappaB regulons, interacting signal pathways and networks are implicated in the malignant phenotype of head and neck cancer cell lines differing in p53 status.

Publications

Systems biology-defined NF-kappaB regulons, interacting signal pathways and networks are implicated in the malignant phenotype of head and neck cancer cell lines differing in p53 status.

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