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

Alastair G. Lowrie, Paul Dickinson, Nicholas Wheelhouse, Grant D. Stewart, Alan J. Ross, Thorsten Forster, James A. Ross

Research output: Contribution to journalArticlepeer-review

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 Ill 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.

Original languageEnglish
Pages (from-to)709-718
Number of pages10
JournalInternational journal of oncology
Volume39
Issue number3
DOIs
Publication statusPublished - Sep 2011

Keywords

  • proliferation
  • oncogene
  • mutagenesis
  • dermcidin
  • microarray
  • NF-KAPPA-B
  • HUMAN PANCREATIC-CANCER
  • TUMOR-NECROSIS-FACTOR
  • IN-VIVO
  • PROSTATE-CANCER
  • SKELETAL-MUSCLE
  • GENE-EXPRESSION
  • MURINE MYOTUBES
  • FACTOR PIF
  • ACTIVATION

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