![]() Many of these features are compatible with the genetic and metabolic events described in aging. ![]() In addition, a developmental or differentiation function has been described for all the family members. The p53 family of transcription factors includes p53, p63 and p73, which are all involved in tumorigenesis as well as in fertility, metabolism, and aging regulation. In response to the increase in the number of new HNSCC cases worldwide, further knowledge of tumour biology and the identification of novel clinical biomarkers are needed to improve prognostic stratification and optimise the anti-cancer therapies. Despite recent diagnostic and therapeutic advances, the prognosis and survival of HNSCC patients remain poor. Head and neck squamous cell carcinoma (HNSCC), the sixth most frequent malignancy worldwide, is a heterogeneous disease that develops from the stratified epithelium of the upper aerodigestive tract. Our findings indicate that aberrant expression of ΔNp63 in HNSSC may act as an oncogenic stimulus by altering the IGF signalling pathway. In addition, a positive correlation was observed between p63 and IRS1 expression in human HNSCC tissue arrays and in publicly available gene expression data. Inactivation of ΔNp63 expression indeed reduces tumour cell responsiveness to IGF1 stimulation, and inhibits the growth potential of HNSCC cells. Here we report that p63 directly controls IRS1 transcription and cellular abundance and fosters the PI3K/AKT and MAPK downstream signalling pathways. Most insulin/IGF1 signalling converges intracellularly onto the protein adaptor insulin receptor substrate-1 (IRS-1) that transmits signals from the receptor to downstream effectors, including the PI3K/AKT and the MAPK kinase pathways, which, ultimately, promote proliferation, invasion, and cell survival. Besides p63, the type 1-insulin-like growth factor (IGF) signalling pathway has been implicated in HNSCC development and progression. Accumulating evidence has proved that deregulation of ΔNp63 expression plays an oncogenic role in head and neck squamous cell carcinomas (HNSCCs).
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