title: Proteolysis-inducing factor core peptide mediates dermcidin-induced proliferation of hepatic cells through multiple signalling networks.
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.
authors.affiliation: Tissue Injury and Repair Group, MRC Centre for Regenerative Medicine, Chancellor's Building, The University of Edinburgh Medical School, Royal Infirmary of Edinburgh, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
authors.forename: Alastair G
authors.initials: AG
authors.lastname: Lowrie
authors.forename: Paul
authors.initials: P
authors.lastname: Dickinson
authors.forename: Nicholas
authors.initials: N
authors.lastname: Wheelhouse
authors.forename: Grant D
authors.initials: GD
authors.lastname: Stewart
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Ross
authors.forename: Thorsten
authors.initials: T
authors.lastname: Forster
authors.forename: James A
authors.initials: JA
authors.lastname: Ross
mesh_terms: D000595:Amino Acid Sequence; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010455:Peptides / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011509:Proteoglycans / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection
chemical_list: D010455:Peptides; D011509:Proteoglycans; C442243:dermcidin; C042057:proteolysis-inducing peptide