Large Liver Cell Dysplasia in Hepatitis B Virus X Transgenic Mouse Liver and Human Chronic Hepatitis B Virus-Infected Liver

Abstract

Objectives: Large liver cell dysplasia (LCD) is frequently associated with hepatitis B virus (HBV), but it remains uncertain whether it is reactive, senescent or preneoplastic. Methods: The HBX transgenic mice and normal control mice were sacrificed at 1, 3, 5, 7, 9, 11, 13 and 15 months after birth. Twenty-three cases of human B viral chronic hepatitis/cirrhosis with prominent LCD were selected. The immunohistochemical stain of proliferating cell nuclear antigen (PCNA), transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay and senescence-associated β-galactosidase (SA-β-Gal) were evaluated. Results: In HBX transgenic mice, LCD was developed since 3 months and formed small nodules of hepatocellular adenoma, which progressed to hepatocellular carcinoma. The hepatocytes with LCD in HBX transgenic mice showed significantly higher PCNA-labeling index (LI) and lower TUNEL-LI than normal hepatocytes of control mice (p < 0.05). In the majority of human B viral chronic hepatitis/cirrhosis, the hepatocytes with LCD revealed higher PCNA-LI and lower TUNEL-LI than those without, when compared in each case using the same tissue block. SA-β-Gal staining showed no difference between hepatocytes with and without LCD. Conclusion: It is suggested that LCD, related to HBV, might not be just an innocent bystander, but closely related to hepatocarcinogenesis.

Large liver cell dysplasia: A controversial entity

“…In the study of chronic B viral hepatitis/cirrhosis, most LCC showed a higher proliferation rate and lower rate of apoptosis than normal hepatocytes, and the difference in proliferation and apoptosis rate, measured in individual cases using the same tissue block, showed a gradual increase in cellular net gain from the hepatocyte without LCC, to those with LCC, to overtly malignant hepatocytes. This result might partly validate LCC as a slowly proliferative but not resting (quiescent) lesion [37]. In addition, the expression of the senescence-associated marker b-galactosidase was positive in only a fraction of large dysplastic hepatocytes [37].…”

Large cell change of hepatocytes in chronic viral hepatitis represents a senescent-related lesion

“…Koo et al [26] demonstrated that hepatocytes with LCC showed a significantly higher proliferating cell nuclear antigen (PCNA) LI in HBV X transgenic mice than did normal hepatocytes of control mice and had a higher PCNA-LI than hepatocytes without LCC, although not significantly, in human CVH-B sections using immunohistochemistry. PCNA protein, a cofactor of DNA polymerase δ, plays an important part in DNA replication in response to DNA damage.…”

HBx induces hypomethylation of distal intragenic CpG islands required for active expression of developmental regulators

“…To examine the DNA methylation changes leading to cancer, we created DNA methylation maps for liver tissues from HBx TG mice and their wild-type littermates at early (3-mo-old) and late (13-mo-old) stages of tumor development (6,19). We sequenced the methylated DNA from at least two independent preparations for each sample using the methylated CpG island recovery assay (MIRA) (20).…”