ETV4 and ETV1-mediated downregulation of the secretory leukocyte protease inhibitor contributes to the indolent phenotype of early-stage prostate cancer

The Secretory Leukocyte Peptidase Inhibitor (SLPI) protects tissues from inflammation but it is overexpressed in various cancers. In prostate cancer (PC) SLPI exhibits a unique biphasic expression pattern: reduced levels in patients with early-stage disease and increased levels in those with advanced disease. Reduced SLPI levels, as in early-stage PC patients, were found in the prostate of a mouse model of early-stage PC, which overexpresses ETV4 into prostate. These reduced SLPI levels were modeled in normal human immortalized prostate RWPE cells by SLPI silencing that resulted, paradoxically, in increase of apoptosis and in decrease of cell migration, invasion, and epithelial-to-mesenchymal transition. Moreover, overexpression and silencing of the members of ETS PEA3-subfamily—ETV4 and ETV1—in human prostate cells (RWPE, PC3, LNCaP) showed that both genes mediate SLPI downregulation. Thus, the reduced levels of SLPI, resulting from ETV4- or ETV1-mediated downregulation, could curb the migratory, invasive, and anti-apoptotic capabilities of prostate cells partially counteracting ETV4 and ETV1 oncogenic effects, thereby contributing to the indolent phenotype of early-stage PC. Furthermore, in the androgen-competent LNCaP cells, androgens upregulate SLPI as well as ETV1, which in turn exerts a negative regulation on SLPI, resulting in a regulatory loop that modulates SLPI levels and explains the biphasic pattern of SLPI expression observed in PC patients. In conclusion, both reduced and increased SLPI levels appear to influence the biological and, possibly, the clinical phenotype of PC. These results uncover a relationship between genetic and microenvironment factors that together shape the evolution and progression of PC.