Dysregulated molecular networks in head and neck carcinogenesis

Abstract

Multiple genetic and epigenetic events, including the aberrant expression and function of molecules regulating cell signaling, growth, survival, motility, angiogenesis, and cell cycle control, underlie the progressive acquisition of a malignant phenotype in squamous carcinomas of the head and neck (HNSCC). In this regard, there has been a recent explosion in our understanding on how extracellular components, cell surface molecules, and a myriad of intracellular proteins and second messenger systems interact with each other, and are organized in pathways and networks to control cellular and tissue functions and cell fate decisions. This emerging ability to understand the basic mechanism controlling inter-and intra-cellular communication has provided an unprecedented opportunity to understand how their dysregulation contributes to the growth and dissemination of human cancers. Here, we will discuss the emerging information on how the use of modern technologies, including gene array and proteomic studies, combined with the molecular dissection of aberrant signaling networks, including the EGFR, ras, NFκB, Stat, Wnt/β-catenin, TGF-β, and PI3K-AKT-mTOR signaling pathways, can help elucidate the molecular mechanisms underlying HNSCC progression. Ultimately, we can envision that this knowledge may provide tremendous opportunities for the diagnosis of premalignant squamous lesions, and for the development of novel molecular-targeted strategies for the prevention and treatment of HNSCC.

NF‐κB inhibition reverses acidic bile‐induced miR‐21, miR‐155, miR‐192, miR‐34a, miR‐375 and miR‐451a deregulations in human hypopharyngeal cells

“…Our novel data demonstrate strong inverted correlations among the BAY 11‐7082‐induced levels of the analysed tumour suppressors” miR‐34a, miR‐375 and miR451a, and NF‐κB‐related genes, such as RELA(p65), STAT3, TNF‐α, IL‐6 and IL‐1β, that previous studies documented as crucial mediators of inflammatory and neoplastic events in head and neck cancer35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 (Figure 7). In line with our recent study,33 our current data suggest that NF‐κB inhibition may reverse acidic bile‐induced molecular events in normal human hypopharyngeal cells that are known to link inflammation to cancer, thereby in a sense shielding HHPC from the effects of bile‐induced oncogenic molecular events.…”

“…Nuclear factor kappa B (NF‐κB) is a key factor that mediates inflammatory and early tumorigenic events in epithelial cells,35 and its importance in initiation and progression of cancer, including head and neck cancer, has been widely supported 23, 36, 37, 38, 39, 40, 41 by its interactions with a complex network of other cancer‐related transcriptional factors, cytokines and growth factors 34, 42, 43, 44, 45, 46. Additionally, Van Waes and Chen recently showed a cluster of genes and miRNA markers that are related to activated NF‐κB and that may contribute to an aggressive phenotype of head and neck cancer 23, 38…”

Expression of EGFR, VEGF, and NOTCH1 Suggest Differences in Tumor Angiogenesis in HPV-Positive and HPV-Negative Head and Neck Squamous Cell Carcinoma

“…This may be attributable to higher EGFR copy number in HPV-negative compared with HPV-positive tumors [33][34][35][36]. EGFR signaling results in activation of several downstream pathways that may affect transcription or translation of VEGF, including the Ras/MAPK, PI3 K/ Akt/mTOR, and STAT3 pathways [37,38]. Of particular note is STAT3, which induces transcription of VEGF in HNSCC cell lines [14].…”

Phosphorylated S6 as an immunohistochemical biomarker of vulvar intraepithelial neoplasia

“…Squamous cell carcinomas typically have hyperactive EGFR/ERK and PI3K/AKT/mTOR signaling pathways. [26][27][28]31 One consequence of activation of these pathways is phosphorylation of the ribosomal protein S6. S6 is a component of the 40S ribosomal subunit and is thought to have a role in modulating efficiency of mRNA translation initiation.…”