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

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

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 over-expression 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 upregula-tion of VEGFB. These data reveal PIF-CP as the key mediator of dermcidin-induced proliferation and demonstrate induction of key oncogenic pathways.

Citation

Lowrie, A. G., Dickinson, P., Wheelhouse, N., Stewart, G. D., Ross, A. J., Forster, T., & Ross, J. A. (2011). Proteolysis-inducing factor core peptide mediates dermcidin-induced proliferation of hepatic cells through multiple signalling networks. International Journal of Oncology, 39(3), 709-18. https://doi.org/10.3892/ijo.2011.1064

• Journal Article Type: Article
• Acceptance Date: May 13, 2011
• Publication Date: Jun 3, 2011
• Deposit Date: Jul 21, 2016
• Publicly Available Date: Jul 25, 2016
• Journal: International Journal of Oncology
• Print ISSN: 1019-6439
• Electronic ISSN: 1791-2423
• Publisher: Spandidos Publications
• Peer Reviewed: Peer Reviewed
• Volume: 39
• Issue: 3
• Pages: 709-18
• DOI: https://doi.org/10.3892/ijo.2011.1064
• Keywords: proliferation, oncogene, mutagenesis, dermcidin, microarray
• Public URL: http://researchrepository.napier.ac.uk/Output/304729
• Related Public URLs: http://www.spandidos-publications.com/ijo/39/3/709/download