Proteolysis-inducing factor core peptide mediates dermcidin-induced proliferation of hepatic cells through multiple signalling networks

Abstract

Abstract. Dermcidin is a candidate oncogene capable of increasing the number of cultured neuronal, breast cancer and prostate cancer cells and improving the survival of hepatic cells. The dermcidin gene encodes the proteolysis-inducing factor core peptide (PIF-CP) and the skin antimicrobial peptide DCD-1. The peptide responsible for inducing proliferation of cells and the mechanisms involved are unknown. In this study, we confirmed a proliferative effect of dermcidin overexpression of 20% (p<0.02) in the HuH7 human hepatic cell line. Proliferation was abrogated by prevention of PIF-CP translation or inactivation of its calcineurin-like phosphatase domain by site-directed mutagenesis. Prevention of DCD-1 translation had no effect. Treatment of cells with a 30 amino acid synthetic PIF-CP induced an analogous increase in proliferation of 14%. Microarray analysis of PIF-CP-treated cells revealed low but significant changes in 111 potential mediator genes. Pathway analysis revealed several gene networks involved in the cellular response to the peptide, one with VEGFB as a hub and two other networks converging on FOS and MYC. Quantitative PCR confirmed direct upregulation of VEGFB. These data reveal PIF-CP as the key mediator of dermcidin-induced proliferation and demonstrate induction of key oncogenic pathways.

Dermcidin expression is associated with disease progression and survival among breast cancer patients

“…To evaluate whether DCD response is associated with tumor aggressiveness, we utilized the publically available breast tumor microarray data NKI-295 to evaluate a previously published signature of genes up- and downregulated with DCD overexpression in HuH7 cells [22]. Patient characteristics for these 295 patients are described in Table 1.…”

“…PIF-CP is identical to neuronal survival factor Y-P30 and is thought to protect cancer cells in the same manner as it protects neuronal cells from damage [28]. DCD leads to multiple gene expression changes that have been suggested to influence cell proliferation, which in turn influence tumor formation and progression [22]. …”

“…However, we also showed interesting biology of DCD-response genes in a population from the Netherlands. The association between DCD response and tumor aggressiveness is interesting in light of the influence that DCD has on cell proliferation [22] and in protecting neuronal cells from damage [29]. …”

“…We examined this by projecting a previously published DCD-derived gene signature onto the publically available breast tumor microarray dataset from the Netherlands Cancer Institute (NKI-295, n = 295) [22]. The DCD expression-based signature was identified by Lowrie et al [22] in HuH7, a hepatic carcinoma cell. These cells do not express DCD, but overexpression of DCD in these cells leads to improved cell survival.…”

Insulin resistance in prostate cancer patients and predisposing them to acute ischemic heart disease

“…Eventually the situation arises where platelets aggregate in the coronary arteries or cerebral arteries culminating an AMI or cerebrovascular stroke, respectively. It has been reported that dermcidin is a cancer cachectic and proteolysis inducing factor (PIF) [42]; it was also found to overexpress in malignant proliferative cells [43]. This stress-induced protein, which was found in the circulation of AMI and ACS patients, was the platelet aggregator and the inhibitor of the aspirin effect through the impairment of nitric oxide [21,22].…”