Opposing functions of psoriasin (S100A7) and koebnerisin (S100A15) in epithelial carcinogenesis

Abstract

The S100 protein family is involved in epithelial cell maturation and inflammation. Some S100 members are dysregulated during carcinogenesis and have been established as tumor markers. Psoriasin (S100A7) and koebnerisin (S100A15) are highly homologous proteins that have been first described in psoriasis, which is characterized by disturbed epidermal maturation and chronic inflammation. Despite their homology, both S100 proteins are distinct in expression and function through different receptors but synergize as chemoattractants and pro-inflammatory 'alarmins' to promote inflammation. Psoriasin and koebnerisin are further regulated with tumor progression in epithelial cancers. In tumor cells, high cytoplasmic expression of psoriasin and koebnerisin may prevent oncogenic activity, whereas their nuclear translocation and extracellular secretion are associated with tumor progression and poor prognosis. The present review outlines these opposing effects of psoriasin and koebnerisin in multifunctional pathways and mechanisms that are known to affect tumor cells ('seeds'), tumor environment ('soil') and tumor cell metastasis ('seeding') thereby influencing epithelial carcinogenesis.

Figure 1.. Multifunctional psoriasin (S100A7) and koebnerisin (S100A15) control the tumour ‘seed’ and ‘soil’

Cellular distribution and release of psoriasin (S100A7) and koebnerisin (S100A15) into the extracellular space effect tumour survival and progression A) Cytoplasmic psoriasin and koebenrisin may protect the tumour cell (‘seed’) from physical (cornified envelope) and biological (AMP) damage, and psoriasin prevents β-catenin translocation to the nucleus and its downstream oncogenic activity. B) In invasive carcinomas, a psoriasin - Jab1 is thought to translocate into the nucleus, to activate AP-1 target genes as well as COP9 signalosome signalling. Psoriasin and likely koebnerisin are secreted into the extracellular space (‘soil’) and act as chemoattractants for tumour-associated inflammatory cells, such as macrophages (TAMs). Their secreted function as ‘alarmins’ by binding to extracellular receptors, such as RAGE, thereby mediating tumor-promoting inflammation. Furthermore, extracellular psoriasin is able to induce tumour cell migration via RAGE. Additionally, extracellular and nuclear distribution of psoriasin leads to a lack of cytoplasmic peptide levels and unlocks the β-catenin-mediated oncogenic signalling.