Am J Pathol. 2019 Aug 23. pii: S0002-9440(19)30670-4. doi: 10.1016/j.ajpath.2019.07.014. [Epub ahead of print]
Repression of death receptor-mediated apoptosis of hepatocytes by Hepatitis B virus e antigen.
Liu W1, Guo TF2, Jing ZT3, Tong QY4.
Author information
1
Institute of Digestive Disease, China Three Gorges University, Yichang, China; Department of Gastroenterology of Yichang Central People's Hospital, Yichang, China. Electronic address: [email protected].
2
Institute of Digestive Disease, China Three Gorges University, Yichang, China.
3
Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China.
4
Institute of Digestive Disease, China Three Gorges University, Yichang, China; Department of Gastroenterology of Yichang Central People's Hospital, Yichang, China. Electronic address: [email protected].
Abstract
Hepatitis B virus (HBV) e antigen (HBeAg) is considered to associate with viral persistence and pathogenesis. Resistance of HBV-infected hepatocytes to apoptosis is seen as one of the primary promotors for HBV chronicity and malignancy. Fas receptor/ligand (Fas/FasL) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) system plays a key role in hepatic death during HBV infection. We find here that HBeAg mediates resistance of hepatocytes to FasL or TRAIL-induced apoptosis. Introduction of HBeAg into human hepatocytes rendered resistance to FasL or TRAIL cytotoxicity in a p53-dependent manner. HBeAg further inhibited the expression of p53, total Fas, membrane-bound Fas, TNF receptor superfamily member 10a (DR4), and TNF receptor superfamily member 10b (DR5) at both mRNA and protein levels. In contrast, HBeAg enhanced the expression of soluble forms of Fas through facilitation of Fas alternative mRNA splicing. In a mouse model, expression of HBeAg in mice injected with recombinant adenovirus-associated virus 8 inhibited agonistic anti-Fas antibody (Jo2)-induced hepatic apoptosis. Xenograft tumorigenicity assay also showed that HBeAg-induced carcinogenesis was resistant to the pro-apoptotic effect of TRAIL and chemotherapeutic drugs. These results indicate that HBeAg may prevent hepatocytes from FasL and TRAIL-induced apoptosis by regulating the expression of pro-apoptotic and anti-apoptotic form of death receptors, which may contribute to the survival and persistence of infected hepatocytes during HBV infection.