We previously showed using microarray profiling biotechnology that stepwise transformation and metastatic progression of SCC in a murine model results in the expression of gene programs related to the signal transcription factor NF-kappaB. Inhibition of NF-kappaB modulated over half the up or down-regulated genes differentially expressed, and attenuated the malignant phenotype, indicating it may be a critical target for prevention or therapy of head and neck cancer. Gene expression profiling and bioinformatic analysis of the promoters of gene clusters differentially expressed in human HNSCC provided evidence for increased prevalence of binding motifs for NF-kappaB as well as other signal transcription factors, such as p53, AP-1, STAT3 and EGR-1 (Yan et al, Genome Biology, 2007). NF-kappaB, p53, AP-1, STAT3 and EGR-1 activation has previously been associated with pathogenesis and therapeutic resistance, and the subsets expressing wt or mt 53 have been reported to differ in response to chemotherapy. These observations suggested the hypothesis that key alterations in a network of signal transcription factors can interact in determining gene expression and development of HNSCC of differing malignant potential and sensitivity or resistance to therapy. Next, we took a systems biology approach to define NF-kappaB regulons, interacting signal pathways and networks in the malignant phenotype of head and neck cancer cell lines differing in p53 status(Yan, Genome Biology, 2008). Unique gene signatures expressed by human 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. An inverse relationship between activation of NF-kB, p53 mutation, and inactivation of TGFbeta pathway and target genes suggested the hypothesis that activation of NF-kB may be linked to alteration of p53 and TGFbeta signaling. We discovered that mt p53 represses TGFbeta receptor II expression, attenuating TGF beta signaling, enhancing inflammatory cytokine responsiveness and activation of NF-kB in HNSCC (Cohen et al, Cancer Res 2009). Another relationship identified was between NF-kB member c-REL and p53 members p53, p63 and p73. This led to demonstration that cytokine TNF induced cREL interacts with p63, displacing p73 from growth arrest and apoptotic genes and the nucleus of HNSCC (Lu et al, Cancer Res, 2011, in press). siRNA knockdown of p63 revealed that it down regulates p53 regulated tumor suppressor genes and upregulated numerous NF-kB related genes, through interaction with c-REL. Novel p63, cREL as well as classical p53 and NF-kB sites were defined in these genes and validated by ChIP assay (Yang et al, Cancer Res, 2010). ChIP sequencing of global gene expression regulated by cREL, p63 and p73 in HNSCC is underway in collaboration with Laboratory of Genetics, NCI. In collaboration with the NCI and Department of Pathology, new proteomic technology, using protein microarrays, was used to analyze EGFR, NF-kB, MAPK, AKT and STAT3 signal phosphoprotein inhibition, and markers of apoptosis in protein extracts from HNSCC lines and specimens from patients in a clinical trial with small molecule inhibitor gefitinib, taxol and radiation.

Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2011
Total Cost
$699,174
Indirect Cost
Name
National Institute on Deafness and Other Communication Disorders
Department
Type
DUNS #
City
State
Country
Zip Code
Cheng, Hui; Yang, Xinping; Si, Han et al. (2018) Genomic and Transcriptomic Characterization Links Cell Lines with Aggressive Head and Neck Cancers. Cell Rep 25:1332-1345.e5
Campbell, Joshua D; Yau, Christina; Bowlby, Reanne et al. (2018) Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas. Cell Rep 23:194-212.e6
Saloura, Vassiliki; Vougiouklakis, Theodore; Sievers, Cem et al. (2018) The role of protein methyltransferases as potential novel therapeutic targets in squamous cell carcinoma of the head and neck. Oral Oncol 81:100-108
Zhang, Yiqun; Kwok-Shing Ng, Patrick; Kucherlapati, Melanie et al. (2017) A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations. Cancer Cell 31:820-832.e3
Derakhshan, Adeeb; Chen, Zhong; Van Waes, Carter (2017) Therapeutic Small Molecules Target Inhibitor of Apoptosis Proteins in Cancers with Deregulation of Extrinsic and Intrinsic Cell Death Pathways. Clin Cancer Res 23:1379-1387
Cancer Genome Atlas Research Network; Albert Einstein College of Medicine; Analytical Biological Services et al. (2017) Integrated genomic and molecular characterization of cervical cancer. Nature 543:378-384
Si, H; Lu, H; Yang, X et al. (2016) TNF-? modulates genome-wide redistribution of ?Np63?/TAp73 and NF-?B cREL interactive binding on TP53 and AP-1 motifs to promote an oncogenic gene program in squamous cancer. Oncogene 35:5781-5794
Eytan, Danielle F; Snow, Grace E; Carlson, Sophie et al. (2016) SMAC Mimetic Birinapant plus Radiation Eradicates Human Head and Neck Cancers with Genomic Amplifications of Cell Death Genes FADD and BIRC2. Cancer Res 76:5442-5454
Cancer Genome Atlas Network (2015) Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 517:576-82
Eytan, Danielle F; Snow, Grace E; Carlson, Sophie G et al. (2015) Combination effects of SMAC mimetic birinapant with TNF?, TRAIL, and docetaxel in preclinical models of HNSCC. Laryngoscope 125:E118-24

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