Abstract
Proteolysis represents a posttranslational modification, which irreversibly changes the structure of targeted proteins. Consequently, peptides generated by proteolytic processing often exhibit a new or altered biological activity. Previous studies from our group and others suggest that the proteolytic balance may be in imbalance upon oral cancer. This has been evidenced by the following: (i) proteinase inhibitors may exhibit reduced abundance in the saliva of oral squamous cell carcinoma (OSCC) patients diagnosed with lymph node metastasis (pN +) and in neoplastic islands from the invasive tumor front; (ii) compared to patients without lymph node metastasis (pN0), pN + patients exhibit accentuated proteolysis of salivary proteins, and the resultant differential peptidome correlated with poor prognostic factors; and (iii) gene expression in tumor tissues reveals that predicted proteinases putatively implicated in the processing of the differential saliva peptidome are associated with poor prognosis and lower survival. Enhanced ADAM17 activity has been associated with inflammation and different types of cancer, such as oral cancer. It belongs to a family of multidomain membrane metalloproteinases that mediate proteolysis of membrane-anchored proteins in various cellular processes. Despite intensive research, there are so far no specific inhibitors available that can be applied in clinical practice. ADAM17 activity is controlled in vivo by different proteins that can act on the catalytic site or in other domains. Our group has investigated ADAM17 role in OSCC through its interactome, and substrates by combining different proteomics, biochemical, and functional-based assays. In summary, this review explores the role of proteolysis in disease, including studies of our group accessing the saliva peptidome as a proteolytic product with prognostic value for patients with OSCC, and likely, ADAM17 regulation, exploring its mechanism of action on OSCC models.
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