Molecular structure, gene expression and functional role of WFDC1 in angiogenesis and cancer.

Whey acidic proteins (WAP) perform a diverse range of important biological functions, including proteinase activity, calcium transport and bacterial growth. The WAP four-disulphide core domain protein 1 (WFDC1) gene (also called PS20), encodes the 20 kDa prostate stromal protein (ps20), which is a member of the WAP-type four-disulphide core domain family of proteins, and exhibits characteristics of serine protease inhibitors, such as elafin and secretory leukocyte protease inhibitor. Molecular structural analysis reveals that ps20 consists of four-disulphide bonds formed by eight cysteine residues located at the carboxyl terminus of the protein. Wfdc1-null mice were found to display no overt developmental phenotype, suggesting a dispensable role in organ growth and development. However, WFDC1 was able to mediate endothelial cell migration and pericyte stabilization, which are vital for the formation of functional vascular structures. WFDC1 was also found to be downregulated in cancers and exhibited a regulatory effect on cell proliferation. In addition, it was involved in the modulation of memory T cells during human immunodeficiency virus infection. Gaining a solid understanding of the mechanisms by which WFDC1 regulates tissue homeostasis and disease processes, in a tissue specific manner, will be an important move towards the development of WFDC1/ps20 as potential therapeutic targets.