Altered inflammatory and death pathways in head and neck cell lines model genomic and expression signatures identified in The Cancer Genome Atlas

Authors

• X Yang
• H Cheng
• A Saleh
• S Cornelius
• E Guven-Maiorov
• O Keskin
• A Gursoy
• R Nussinov
• C Van Waes
• Z Chen

Abstract

The Cancer Genome Atlas (TCGA) project has investigated 279 HNSCC tissue specimens, and uncovered significant genomic alterations of key molecules involved in inflammation, NF-B, and death pathways. Using bioinformatic analyses and protein structural and interactive tools, we identified ~60 proteins that may be potentially involved in the inflammation and death pathways. More than 90% HNSCC tissues studied in TCGA exhibited expression or genetic alterations of these genes, with FADD amplification and/or overexpression ranking first with 37%. Among more than 20 major cancer types investigated by TCGA, HNSCC ranked the highest for theses alterations. Furthermore, we performed whole transcriptome (RNA-seq) and genome-wide exome DNA sequencing (exome DNA-seq) in 15 HPV(-) and 11 HPV(+) HNSCC lines, and compared them with three normal human oral mucosa lines and 8 matched blood samples. We have identified gene amplifications and overexpression among many of the molecules involved in inflammation, NF-B and death pathways in cell lines, which were observed in the HNSCC TCGA project. Next, we established HNSCC cell lines stably transfected with a vector that contains -lactamase reporter gene for NF-B activation. Using these NF-B reporter cell lines, large RNAi screening assays have been performed to assess the regulatory and signaling molecules involve in NF-κB and death pathways to model the findings from TCGA. The function and mechanistic validation of these molecules are under the way, which could provide precise molecular targets of diagnosis and prognosis for further preclinical and clinical investigation in HNSCC.

Scientific Focus Area: Cancer Biology

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