Li Yong, Gan Lipeng, Lu Min, Zhang Xiaodan, Tong Xiaomei, Qi Dandan, Zhao Yan, Ye Xin
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China.
FASEB J. 2023 Apr;37(4):e22871. doi: 10.1096/fj.202200999RR.
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.
乙型肝炎病毒（HBV）是诱发肝癌发生和发展的重要危险因素之一，但其机制尚未完全阐明。在本研究中，我们发现与HepG2相比，在HBV转基因细胞系HepG2-4D14中核心蛋白聚糖（DCN）显著减少。来自肝细胞癌（HCC）患者的数据表明，肿瘤组织中DCN mRNA水平显著低于健康对照，且与HCC患者的生存率呈正相关。我们发现HBV的X蛋白（HBx）可通过阻断p53活性来抑制DCN的转录。功能分析表明，DCN的过表达可显著抑制HCC细胞的增殖，而敲低DCN则增强HCC细胞的增殖。已知DCN可竞争性结合c-Met以抑制HGF/c-Met信号通路，从而抑制HCC的发展。因此，我们基于DCN的序列以及HGF/c-Met的复杂结构，通过虚拟筛选从DCN中筛选出新型抗肿瘤肽，并鉴定出一组可能竞争性结合c-Met的DCN衍生肽（DCN-Ps）。我们发现其中5种肽可显著降低HepG2细胞的增殖和迁移。其中，DCN-P#3在体外和体内均可抑制HCC细胞的生长。总之，我们发现HBV的HBx下调DCN的表达，进而促进肝细胞的增殖和HCC的发展。我们鉴定出DCN衍生的抗肿瘤肽，为开发抗HCC新药提供了候选药物。
