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

Yuan Chi Teng, Jenq Chyuan Neo, Jaw Ching Wu, Yi Fan Chen, Cheng Heng Kao, Ting Fen Tsai

Research output: Contribution to journalArticle

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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-preΔS2 transgenic mice that express a naturally occurring pre-S2 mutant protein containing a 33-nucleotide deletion (preΔS2); 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 months 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 kinase RNA-like endoplasmic reticulum kinase (PERK) pathway of the UPR was induced and the Hippo transducer Yap was activated. Together, these ultrastructural aberrations and metabolic disturbance all seem to contribute to the molecular pathogenesis and hepatocarcinogenesis present in the Alb-preΔS2 mice. These findings may contribute to the development of therapies for the liver disorders and HCC associated with pre-S2 deletion mutations among HBV carriers.

Original languageEnglish
Pages (from-to)463-474
Number of pages12
JournalJournal of Pathology
Volume241
Issue number4
DOIs
Publication statusPublished - Mar 1 2017

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Hepatomegaly
Hepatitis B virus
Hepatocellular Carcinoma
Endoplasmic Reticulum
Liver
Unfolded Protein Response
Fibrosis
Inflammation
Rectal Prolapse
B-Lymphocyte Epitopes
Mevalonic Acid
Endoplasmic Reticulum Stress
Peroxisomes
Sequence Deletion
Virus Diseases
Mutant Proteins
Liver Neoplasms
Hepatitis B Surface Antigens
Metabolic Networks and Pathways
Transducers

Keywords

  • HBV
  • hepatitis B virus
  • hepatocellular carcinoma
  • hepatomegaly
  • large surface antigen
  • pre-S2 mutant
  • transgenic mice

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Expression of a hepatitis B virus pre-S2 deletion mutant in the liver results in hepatomegaly and hepatocellular carcinoma in mice. / Teng, Yuan Chi; Neo, Jenq Chyuan; Wu, Jaw Ching; Chen, Yi Fan; Kao, Cheng Heng; Tsai, Ting Fen.

In: Journal of Pathology, Vol. 241, No. 4, 01.03.2017, p. 463-474.

Research output: Contribution to journalArticle

Teng, Yuan Chi ; Neo, Jenq Chyuan ; Wu, Jaw Ching ; Chen, Yi Fan ; Kao, Cheng Heng ; Tsai, Ting Fen. / Expression of a hepatitis B virus pre-S2 deletion mutant in the liver results in hepatomegaly and hepatocellular carcinoma in mice. In: Journal of Pathology. 2017 ; Vol. 241, No. 4. pp. 463-474.
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