Dermcidin Enhances the Migration, Invasion, and Metastasis of Hepatocellular Carcinoma Cells In Vitro and In Vivo

Abstract

Background and AimsHepatocellular carcinoma (HCC) is a common primary liver neoplasm with high mortality. Dermcidin (DCD), an antimicrobial peptide, has been reported to participate in oncogenesis. This study assessed the effects and underlying molecular events of DCD overexpression and knockdown on the regulation of HCC progression in vitro and in vivo.MethodsThe serum DCD level was detected using enzyme-linked immunosorbent assay. DCD overexpression, knockdown, and Ras-related C3 botulinum toxin substrate 1 (Rac1) rescue were performed in SK-HEP-1 cells using plasmids. Immunofluorescence staining, quantitative PCR, and Western blotting were used to detect the expression of different genes and proteins. Differences in HCC cell migration and invasion were detected by Transwell migration and invasion assays. A nude mouse HCC cell orthotopic model was employed to verify the in vitro data.ResultsThe level of serum DCD was higher in patients with HCC and in SK-HEP-1 cells. DCD overexpression caused upregulation of DCD, fibronectin, Rac1, and cell division control protein 42 homologue (Cdc42) mRNA and proteins as well as actin-related protein 2/3 (Arp2/3) protein (but reduced Arp2/3 mRNA levels) and activated Rac1 and Cdc42. Phenotypically, DCD overexpression induced HCC cell migration and invasion in vitro, whereas knockout of DCD expression had the opposite effects. A Rac1 rescue experiment in DCD-knockdown HCC cells increased HCC cell migration and invasion and increased the levels of active Rac1/total Rac1, Wiskott-Aldrich syndrome family protein (WASP), Arp2/3, and fibronectin. DCD overexpression induced HCC cell metastasis to the abdomen and liver in vivo.ConclusionsDCD promotes HCC cell migration, invasion, and metastasis through upregulation of noncatalytic region of tyrosine kinase adaptor protein 1 (Nck1), Rac1, Cdc42, WASP, and Arp2/3, which induce actin cytoskeletal remodeling and fibronectin-mediated cell adhesion in HCC cells.