HBx downregulated decorin and decorin-derived peptides inhibit the proliferation and tumorigenicity of hepatocellular carcinoma cells

Abstract

Hepatitis B virus (HBV) is one of the important risk factors in inducing the occurrence and development of liver cancer, while the mechanism has not been fully clarified. In this study, we found decorin (DCN) was significantly reduced in HBV transgenic cell line HepG2-4D14 compared to HepG2. The data from hepatocellular carcinoma (HCC) patients indicated that the level of DCN mRNA was significantly lower in tumor tissues than healthy control and positively correlated with the survival of HCC patients. We revealed that HBV HBx can inhibit the transcription of DCN by blocking p53 activity. Functional analysis demonstrated that overexpression of DCN substantially inhibits the proliferation of HCC cells, while knockdown of DCN enhances the proliferation of HCC cells. It is known that DCN could competitively bind to c-Met to inhibit HGF/c-Met signaling pathway to inhibit the development of HCC. Therefore, we screened the novel antitumor peptides derived from DCN based on the sequence of DCN and the complex structure of HGF/c-Met with virtual screening and identified a set of DCN-derived peptides (DCN-Ps) which may competitively bind to c-Met. We found that 5 of peptides can reduce the proliferation and migration of HepG2 cells significantly. Among them, DCN-P#3 can inhibit the growth of HCC cells both in vitro and in vivo. In conclusion, we discovered that HBV HBx downregulates the expression of DCN, which in turn promotes the proliferation of hepatocytes and the development of HCC. We identified DCN-derived antitumor peptides which provides the candidates for developing novel drugs against HCC.

Keywords: antitumor peptides; decorin; hepatitis B virus; hepatocellular carcinoma; virtual screening.