Signaling Networks of Activated Oncogenic and Altered Tumor Suppressor Genes in Head and Neck Cancer

Abstract

Head and neck squamous cell carcinoma (HNSCC) arises from the upper aerodigestive tract and is the six most common cancers worldwide. HNSCC is associated with high morbidity and mortality, as standard surgery, radiation, and chemotherapy can cause significant disfigurement and only provide 5-year survival rates of ~50-60%. The heterogeneity of HNSCC subsets with different potentials for recurrence and metastasis challenges the traditional pathological classification system, thereby increasing demand for the development of new diagnostic, prognostic, and therapeutic tools based on global molecular signatures of HNSCC. Historically, using classical biological techniques, it has been extremely difficult and time-consuming to survey hundreds or thousands of genes in a given disease. However, the development of high throughput technologies and high-powered computation throughout the last two decades has enabled us to investigate hundreds or thousands of genes simultaneously. Using high throughput technologies, our laboratory has identified the gene signatures and protein networks, which significantly affect HNSCC malignant phenotypes, including TP53/p63/p73 family members, IL-1/TNF-β/NF-κB, PI3K/AKT/mTOR, IL-6/IL-6R/JAK/STAT3, EGFR/MAPK/AP1, HGF/cMET/EGR1, and TGFβ/TGFβR/TAK1/SMAD pathways. This review summarizes the results from high-throughput technological assays conducted on HNSCC samples, including microarray, DNA methylation, miRNA profiling, and protein array, using primarily experimental data and conclusions generated in our own laboratory. The use of bioinformatics and integrated analyses of data sets from different platforms, as well as meta-analysis of large datasets pulled from multiple publicly available studies, provided significantly higher statistical power to extract biologically relevant information. The data suggested that the heterogeneity of HNSCC genotype and phenotype are much more complex than we previously thought. Understanding of global molecular signatures and disease classification for specific subsets of HNSCC will be essential to provide accurate diagnoses for targeted therapy and personalized treatment, which is an important effort toward improving patient outcomes.