Head and Neck Cancers Promote an Inflammatory Transcriptome through Coactivation of Classic and Alternative NF-κB Pathways

Abstract

Head and neck squamous cell carcinomas (HNSCC) promote inflammation in the tumor microenvironment through aberrant NF-κB activation, but the genomic alterations and pathway networks that modulate NF-κB signaling have not been fully dissected. Here, we analyzed genome and transcriptome alterations of 279 HNSCC specimens from The Cancer Genome Atlas (TCGA) cohort and identified 61 genes involved in NF-κB and inflammatory pathways. The top 30 altered genes were distributed across 96% of HNSCC samples, and their expression was often correlated with genomic copy number alterations (CNA). Ten of the amplified genes were associated with human papilloma virus (HPV) status. We sequenced 15 HPV(−) and 11 HPV(+) human HNSCC cell lines, and three oral mucosa keratinocyte lines, and supervised clustering revealed that 28/61 genes exhibit altered expression patterns concordant with HNSCC tissues, and distinct signatures related to their HPV status. RNAi screening using an NF-κB reporter line identified 16 genes that are induced by TNF-α or Lymphotoxin β (LTβ) and implicated in the classical and/or alternative NF-κB pathways. Knockdown of TNFR, LTΒR, or selected downstream signaling components established cross-talk between the classical and alternative NF-κB pathways. TNF-α and LTβ induced differential gene expression involving the NF-κB, IFN-γ and STAT pathways, *

Regulation of NFκB Signalling by Ubiquitination: A Potential Therapeutic Target in Head and Neck Squamous Cell Carcinoma?

“…The difference in clinical response of HPV+ and HPV− HNSCC is not fully understood; however, recent developments in the genomic and transcriptomic analysis of primary HNSCC cases have provided insight into the difference in clinical response [ 14 , 17 ]. Subsequent studies have examined the alterations in specific pathways and how these relate to the pathogenesis of HNSCC and have highlighted a critical role for aberrant NFκB activity.…”

“…The activation of NFκB in HNSCC occurs through various mechanisms, including somatic mutations, genetic copy number alterations (CNA), or the expression of the HPV viral oncogenes [ 14 , 19 , 20 ]. Several genome wide studies have highlighted the prevalence of several alterations in the ubiquitin system implicated in the aberrant activation of NFκB signalling in HNSCC ( Table 2 ).…”

“…BIRC2 is more commonly amplified and overexpressed in HPV- HNSCC, while BIRC3 overexpression appears to be more common in HPV+ HNSCC [ 109 ]. Additional ubiquitin components are upregulated at the mRNA level; OTUB1 mRNA levels are high in HNSCC, without significant copy number alterations [ 14 ].…”

“…Inflammatory conditions can induce signalling and genetic damage to initiate or promote tumorigenesis; furthermore, genetic and epigenetic changes, as well as the HPV oncogenes, can generate an inflammatory microenvironment that further supports tumor progression [ 6 , 13 ]. Many inflammatory cytokines and signalling pathways are implicated in the pathogenesis of HNSCC [ 14 , 15 ]; the expression of these inflammatory mediators and intrinsic resistance of tumor cells can be driven by the oncogenic insults known to contribute to the development of HNSCC [ 14 , 16 , 17 ].…”

“…An important driver and inducer of inflammatory mediators, which promotes cell survival and therapeutic resistance, is the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) [ 18 ]. In HNSCC, NFκB is often aberrantly activated and is a common mediator of the effects of numerous pro-inflammatory cytokines (TNFα and IL-1), as well as other signalling pathways targeted by oncogenic mutations, genetic copy number alterations (CNA), or viral oncogenes [ 14 , 19 , 20 ]. NFκB drives the expression of a repertoire of genes that promote malignant progression, including cell proliferation and survival, therapeutic resistance, and pro-inflammatory factors [ 21 , 22 ].…”