Expression of a hepatitis B virus pre ‐S2 deletion mutant in the liver results in hepatomegaly and hepatocellular carcinoma in mice

Abstract Hepatocellular carcinoma (HCC) is the most common form of liver cancer and has a poor prognosis and a low survival rate; its incidence is on the rise. Hepatitis B virus (HBV) infection is one of the main causes of HCC. A high prevalence of pre‐S deletions of HBV surface antigen, which encompass T‐cell and/or B‐cell epitopes, is found in HBV carriers; antiviral therapy and viral immune escape may cause and select for these HBV mutants. In particular, the presence of pre‐S2 deletion mutants is an important risk factor associated with cirrhosis and HCC. We generated Alb‐pre∆S2 transgenic mice that express a naturally occurring pre‐S2 mutant protein containing a 33‐nucleotide deletion (pre∆S2); the aim was to investigate its effect on hepatocarcinogenesis. After 30 months of follow‐up, the liver pathology of the mice fell into four groups; G1, chronic inflammation solely; G2, chronic inflammation and fibrosis; G3, inflammation, fibrosis and hepatomegaly accompanied by rectal prolapse (4%‐12%); and G4, hepatomegaly and spontaneous HCC (12%‐15%). Striking degeneration of the endoplasmic reticulum (ER) was present in the mouse livers at an early stage (4‐month old). At 8 months, overt ER stress and the Atf6 pathway of the unfolded protein response (UPR) were induced; at the same time metabolic pathways associated with mevalonate and cholesterol biogenesis, involving the peroxisomes and the ER, were disturbed. At 20 months and older, the protein kin...
Source: The Journal of Pathology - Category: Pathology Authors: Tags: Original Paper Source Type: research