Gene Expression Analysis in HBV Transgenic Mouse Liver: A Model to Study Early Events Related to Hepatocarcinogenesis

Barone, M.; Spano, Daniela; D’Apolito, Maria; Centra, Michele; Lasalandra, Carla; Capasso, Mario; Leo, Alfredo Di; Volinia, Stefano; Arcelli, Diego; Rosso, Natalia; Francavilla, A.; Tiribelli, Claudio; Iolascon, Achille

doi:10.2119/2006-00015.barone

Cited by 31 publications

(23 citation statements)

References 63 publications

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“…Indeed, the expression of HLA class II molecules is an important part of the mechanism leading to the activation of the inflammatory response involved in the progression and severity of HBeAg-negative CHB infection. Data obtained from gene expression analysis in HBV-transgenic mice showed an overexpression of HLA class II molecules that induces hepatocarcinogenesis (4). We found that HLA class-II staining was more intense in patients with a higher necroinflammatory grade, consistent with the effects of HLA class II molecules on cellular damage following the immune response.…”

Section: Discussionsupporting

confidence: 74%

Downregulation of HLA Class II Molecules by G1896A Pre-Core Mutation in Chronic Hepatitis B Virus Infection

et al. 2009

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Over the past decade, increasing attention has been focused on the contribution of naturally occurring mutations in the hepatitis B virus (HBV) genome to the clinical course of the chronic infection. The aim of this study was to investigate the effect of the HBV pre-core mutation G1896A on the expression of HLA class II molecules and the core protein of hepatitis B in liver biopsies of chronic hepatitis B (CHB) infection. In 30 HBeAg-negative CHB patients the pre-core region of the HBV genome was amplified and sequenced to determine the presence of the mutation G1896A. Liver biopsies were scored based on the Histology Activity Index (HAI) system and immunohistochemistry (IHC) was performed to study the expression of HLA class II molecules on the antigen-presenting cells and the core protein in hepatocytes. We found that 19 of the 30 patients (63%) harbored the G1896A mutation. Compared to the patients without this mutation, those with G1896A had lower HAI scores (5.0 +/- 2.8 versus 7.9 +/- 4, p = 0.03). The study of the expression of HLA-II molecules in our patients revealed that subjects with the G1896A mutation had lower expression of HLA-II compared to wild-type infected subjects (1.87 +/- 0.6 versus 3.27 +/- 1.5, p < 0.01). Core protein expression was present in four patients (13.3%) who had higher HBV DNA levels than patients without core protein expression (3.81 +/- 0.78 versus 2.02 +/- 0.16, p < 0.001). These results suggest that the G1896A pre-core mutation may directly interfere with antigen presentation, most likely by decreasing the availability of HLA class II molecules, and this may result in less aggressive liver disease in HBeAg-negative CHB infection.

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Section: Discussionsupporting

confidence: 74%

Downregulation of HLA Class II Molecules by G1896A Pre-Core Mutation in Chronic Hepatitis B Virus Infection

et al. 2009

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“…Starting from 3 months, these mice show a dysregulation in genes involved in apoptosis, cell cycle, NF-κB pathway, and inflammatory response 10 .…”

Section: Discussionmentioning

confidence: 99%

Activation of hepatic stem cells compartment during hepatocarcinogenesis in a HBsAg HBV-transgenic mouse model

Anfuso

El-Khobar

et al. 2018

Sci Rep

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Chronic infection of Hepatitis B Virus (HBV) is one of the highest risk factors of hepatocellular carcinoma (HCC). The accumulation of HBV surface antigen (HBsAg) into hepatocytes induces inflammation and oxidative stress, impairing their replicative ability and allowing the activation of the hepatic stem cells (SC) compartment. This study aimed to understand the involvement of SC during hepatocarcinogenesis in HBsAg-related liver damage, from early injury until HCC. HBsAg-transgenic (TG) and wild type (WT) mouse were followed at several stages of the liver damage: inflammation, early hepatocytes damage, dysplasia, and HCC. Serum transaminases, liver histology, and diagnostic data were collected. The expressions of SC and cancer stem cells (CSC) markers was analyzed by RT-qPCR, immunohistochemistry and Western blot. Starting from 3 months, TG animals showed a progressive liver damage characterized by transaminases increase. The up-regulations of SCs markers Cd34 and Sca-1 started from the beginning of the inflammatory stage while progressive increase of Krt19 and Sox9 and CSCs markers Epcam and Cd133 from early hepatic injury. The expressions of Cd133, Cd34, and Afp were significantly higher in HCC compared to paired non-HCC tissue, in contrast to Epcam and Krt19. Western blot and IHC confirmed the positivity of Cd34 and Cd133 in small cells subpopulation.

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“…Type I GGHs harbour mutants with deletions within the pre‐S1 region (mutated L protein), whereas type II GGHs contain pre‐S2 mutants and are distributed in clusters, showing patterns of proliferative nodules . Over two decades ago, a mouse model over‐expressing the HBV large envelope polypeptide (L), PreS1 and parts of HBx was shown to have liver cell injury, inflammation and compensatory proliferation, finally progressing to HCC due to apoptotic dysregulation . This was also found in HBV transgenic mouse models expressing mutated preS2 .…”

Section: Hbs Antigen and Pre‐s/s Mutants In Hcc Development: Link To Uprmentioning

confidence: 99%

The direct and indirect roles of HBV in liver cancer: prospective markers for HCC screening and potential therapeutic targets

Ringelhan

O’Connor

Protzer

et al. 2014

The Journal of Pathology

121

108

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Chronic hepatitis B virus (HBV) infection remains the number one risk factor for hepatocellular carcinoma (HCC), accounting for more than 600 000 deaths/year. Despite highly effective antiviral treatment options, chronic hepatitis B (CHB), subsequent end-stage liver disease and HCC development remain a major challenge worldwide. In CHB, liver damage is mainly caused by the influx of immune cells and destruction of infected hepatocytes, causing necro-inflammation. Treatment with nucleoside/nucleotide analogues can effectively suppress HBV replication in patients with CHB and thus decrease the risk for HCC development. Nevertheless, the risk of HCC in treated patients showing sufficient suppression of HBV DNA replication is significantly higher than in patients with inactive CHB, regardless of the presence of baseline liver cirrhosis, suggesting direct, long-lasting, predisposing effects of HBV. Direct oncogenic effects of HBV include integration in the host genome, leading to deletions, cis/trans-activation, translocations, the production of fusion transcripts and generalized genomic instability, as well as pleiotropic effects of viral transcripts (HBsAg and HBx). Analysis of these viral factors in active surveillance may allow early identification of high-risk patients, and their integration into a molecular classification of HCC subtypes might help in the development of novel therapeutic approaches.

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Gene Expression Analysis in HBV Transgenic Mouse Liver: A Model to Study Early Events Related to Hepatocarcinogenesis

Cited by 31 publications

References 63 publications

Downregulation of HLA Class II Molecules by G1896A Pre-Core Mutation in Chronic Hepatitis B Virus Infection

Downregulation of HLA Class II Molecules by G1896A Pre-Core Mutation in Chronic Hepatitis B Virus Infection

Activation of hepatic stem cells compartment during hepatocarcinogenesis in a HBsAg HBV-transgenic mouse model

The direct and indirect roles of HBV in liver cancer: prospective markers for HCC screening and potential therapeutic targets

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