Abstract
β-defensin family plays a role in host defense against viral infection, however its role in HCV infection is still unknown. In this study, we demonstrated that β-defensin 1 was significantly reduced in HCV-infected liver specimens. Treatment with interferon and ribavirin upregulated β-defensin-1, but not other β-defensin tested, with the extent and duration of upregulation associated with treatment response. We investigated β-defensin family expression in liver cancer in publicly available datasets and found that among all the β-defensins tested, only β-defensin 1 was significantly downregulated, suggesting β-defensin 1 plays a crucial role in liver cancer development. Further analysis identified E-cadherin as the top positive correlated gene, while hepatocyte growth factor-regulated tyrosine kinase substrate as the top negative correlated gene. Expression of two proteoglycans were also positively correlated with that of β-defensin 1. We have also identified small molecules as potential therapeutic agents to reverse β-defensin 1-associated gene signature. Furthermore, the downregulation of β-defensin 1 and E-cadherin, and upregulation of hepatocyte growth factor-regulated tyrosine kinase substrate, were further confirmed in liver cancer and adjacent normal tissue collected from in-house Chinese liver cancer patients. Together, our results suggest β-defensin 1 plays an important role in protecting HCV progression and liver cancer development.
Highlights
Defensin family is a group of small, disulphide-rich, cationic peptides, with highly diverse sequences and structures among eukaryotes
We found that CDH1 expression was significantly and consistently downregulated in liver cancer specimens compared to non-tumor specimens in GSE25097 (Fig. 6A; P < 0.001), GSE14520 (Fig. 6B; P < 0.001) and GSE36376 (Fig. 6C; P < 0.001), while hepatocyte growth factor-regulated tyrosine kinase substrate (HGS) expression was significantly and consistently upregulated in liver cancer specimens compared to non-tumor specimens in GSE25097 (Fig. 6D; P < 0.001), GSE14520 (Fig. 6E; P < 0.001) and GSE36376 (Fig. 6F; P < 0.001)
We have shown that DEFB1 was downregulated in HCV-infected specimens, while it was upregulated by treatment of interferon and ribavirin, and the degree and duration of upregulation of DEFB1 predicted the response to treatment
Summary
Defensin family is a group of small, disulphide-rich, cationic peptides, with highly diverse sequences and structures among eukaryotes. There were 31 human β-defensin genes found, while β-defensin 1 (DEFB1) is recognized as the most important anti-microbial peptide in epithelial cells, with its action directed against both Gram-negative bacteria and fungal Candidia species. Β-defensin 1 expression was decreased in HCV-infected patients, and that interferon treatment modulated β-defensin 1 expression and this modulation may predict the response to interferon treatment Further analyzing these patient cohorts resulted in identification of genes that are co-regulated with β-defensin 1 and small molecules that could reverse the cancer specific β-defensin 1-mediated gene signature
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