A novel mouse model of hepatocellular carcinoma mediated by hepatitis B virus-specific CD8+ T cells [bulk RNA-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE130668 | GEO | 2023/04/21
REPOSITORIES: GEO
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Project description:We used immunocompetent Fah-/- mice as the recipients and adoptively transferred HBsAg+ hepatocytes from HBs-Tg mice to replace the recipient hepatocytes (HBs-HepR). HBs-HepR mice maintained persistent HBsAg expression with chronic hepatitis and spontaneous liver fibrosis, and eventually developed HCC with a prevalence of 100%.
2020-04-28 | GSE130880 | GEO
Project description:Background and Aims: Chronic hepatitis B virus (HBV) infection is the leading cause of hepatocellular carcinoma (HCC) and is a serious health problem in China, East Asia, and North African countries. Effective treatment of HBV-related HCC is currently unavailable. This study evaluated the therapeutic potential of TIGIT blockade in HBV-related HCC. Approach and Results: A mouse model of spontaneous HBV-related HCC was generated by replacing wild-type hepatocytes with HBsAg+ hepatocytes (namely HBs-HepR mice). The tumors in HBs-HepR mice were inflammation-associated HCC, similar to HBV-related HCC in patients, which was distinguished from other HCC mouse models, such as diethylnitrosamine (DEN)-induced HCC, Tak1-knockout-induced HCC, HCC in stelic animal model (STAM), or nonalcoholic steatohepatitis (NASH)-induced HCC. HCC in HBs-HepR mice was characterized by an increased number of CD8+T cells whereas the production of IL-2, TNF-α, and IFN-γ by intrahepatic CD8+T cells was decreased. Increased expression of TIGIT on CD8+T cells was responsible for functional exhaustion. The therapeutic effect of TIGIT blockade was investigated at the early and middle stages of HCC progression in HBs-HepR mice. TIGIT blockade reinvigorated intrahepatic CD8+T cells with increased TNF-α and IFN-γ production and an increased number of CD8+T cells in tumors, thereby slowing the development of HCC in HBs-HepR mice. Blocking PD-L1 did not show direct therapeutic effects or synergize with TIGIT blockade. Conclusions: Blockade of TIGIT alone enhanced the anti-tumor activity of CD8+T cells during the progression of HBV-related HCC in a spontaneous HCC mouse model.
2022-12-31 | GSE209856 | GEO
Project description:Search for distinct genes whose expression correlates with IFN⍺ mediated liver injury in HBsAg-Tg mice. IFN treatment induces liver injury from 8 hours post IFN treament, peaking at 24 hours, in HBs transgenic mice and not in the non-transgenic (control) mice
2019-10-16 | GSE138916 | GEO
Project description:Fumarylacetoacetate hydrolase (Fah), the last enzyme of the tyrosine degradation pathway, is specifically expressed in hepatocytes in the liver. Loss of Fah leads to liver failure in mice within 6-8 weeks. This can be prevented by blocking tyrosine degradation upstream of Fah with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC). Here, we investigate the impact of p21 on global gene expression in Fah deficiency. Experiment Overall Design: Livers from adult wildtype, Fah or Fah, p21 knockout mice were analyzed either after continuous treatment (ON) with NTBC or after NTBC withdrawal for 14 days (OFF).
2008-06-11 | E-GEOD-11098 | biostudies-arrayexpress
Project description:Fah-/-, Rag2-/-, IL2Rg-/-, non-obese diabetic (FRG-NOD) mice transplanted with primary human hepatocytes were infected with 10^9 HBV genome equivalents purified from concentrated supernatant of the HepG2.2.15 cell line (HBV genotype D subtype ayw). Eight weeks later mice were treated twice a day by intraperitoneal injection of either vehicle or 100 mg/kg SR9009 for 2 weeks. At the end of experiment, mouse livers were collected for RNA-seq analysis. The sequence reads were mapped to the human or mouse genome.
2020-12-16 | GSE163285 | GEO
Project description:Over half of the mature hepatocytes in mice and humans are aneuploid and yet retain full ability to undergo mitosis. This observation has raised the question whether this unusual somatic genetic variation evolved as an adaptive mechanism to hepatic injury. According to this model, hepatotoxic insults would select for hepatocytes with specific numerical chromosome abnormalities, rendering them differentially resistant to the injury. To test this hypothesis, we utilized a strain of mice heterozygous for a mutation in homogentisic acid dioxygenase (Hgd), located on chromosome 16. Loss of this allele can protect from fumarylacetoacetate hydrolase (Fah) deficiency. When adult Hgd+/- Fah-/- mice were exposed to chronic liver damage, injury-resistant nodules consisting of Hgd-null hepatocytes rapidly emerged. To determine whether aneuploidy played a role in this phenomenon, array comparative genomic hybridization (aCGH) and metaphase karyotyping were performed. Strikingly, loss of chromosome 16 was dramatically enriched in all mice that became completely resistant to tyrosinemia-induced hepatic injury. The frequency of chromosome 16-specific aneuploidy was ~50%. This result provides proof-of-principle that the selection of a specific aneuploid karyotype can result in the adaptation of hepatocytes to chronic liver injury. The extent to which aneuploidy promotes hepatic adaptation in humans is under investigation. 8 mouse hepatocyte samples were analyzed. Genomic DNA samples were derived from wild type mice (2), Hgd-/- Fah-/- mice off NTBC (2) and Hgd+/- Fah-/- off NTBC (4). Samples were compared to sex-mismatched reference genomic DNA isolated from wild type mouse splenocytes.
2012-07-16 | E-GEOD-38963 | biostudies-arrayexpress
Project description:Hepatitis B virus (HBV) can integrate into the chromosomes of infected hepatocytes, contributing to the production of hepatitis B surface antigen (HBsAg) and to hepatocarcinogenesis. We performed spatial transcriptomics to investigate the intrahepatic cell heterogeneity and the spatial distribution of transcriptionally active HBV integration events in different phases of chronic HBV infection. Our analysis revealed that transcriptionally active HBV integration occurred in chronically HBV-infected patients in different phases, including those patients with HBsAg loss, and antiviral treatment was associated with a decreased number and extent of viral integrations.
2023-09-30 | GSE243367 | GEO
Project description:Fumarylacetoacetate hydrolase (Fah), the last enzyme of the tyrosine degradation pathway, is specifically expressed in hepatocytes in the liver. Loss of Fah leads to liver failure in mice within 6-8 weeks. This can be prevented by blocking tyrosine degradation upstream of Fah with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC). Here, we investigate the impact of p21 on global gene expression in Fah deficiency. Keywords: treatment, genotype
2008-04-09 | GSE11098 | GEO
Project description:The goal of this experiment was to test whether human hepatocytes could give rise to biliary-like progenitor cells in an in vivo context. Here Fah-/- Il2ry-/- Rag2-/-NOD mouse livers were humanized with human hepatocytes. Only hepatocytes engraft in the Fah-/- mouse at detectable levels in this model. Then animals were given chronic liver injury with 0.1% ddc. After injury we measured human-specific transcripts to determine whether the phenotype of the human cells had changed. Specifically, we evaluated the relative levels of human biliary duct markers such as Spp1, Sox9, Krt7, etc. and hepatocyte markers such as Alb, Ttr, Fah, etc. 3 DDC treated chimeras and 6 untreated chimeras are included. Additional controls include a normal human liver biopsy, FACS sorted primary intrahepatic human bile duct cells, mouse hepatocytes, and mouse intrahepatic biliary cells in ddc treated animal.
2014-09-01 | E-GEOD-58679 | biostudies-arrayexpress
Project description:In patient serum, HBsAg particles can outnumber HBV particles by 1000:1 or higher. To explore the interactions between HBsAg and hepatocytes, concentrating on the possible effects of persistently secreting HBsAg on the functions of host cells, we have used the S gene of a full-length HBV isolate derived from an HBsAg chronic carrier (code No. C8, GenBank accession No. AF461363), cloned into pCMV vector to transfect HepG2 cells. G418 resistant clones secreting HBsAg were selected to establish permanent cell lines, and control clones transfected only with the vector were passaged as well to serve as controls. Cells were separately collected on the fourth and the eighth day after seeding, and gene expression profiles of both cell clones were studied and compared by microarray. Totally, 340 genes were suppressed and 673 genes were induced by the expression of HBsAg on the fourth day, whereas 219 genes were down-regulated and 683 genes were up-regulated on the eighth day. Arbitrarily, changes of genes detected on both 4th and 8th day cultures were selected for further study. Many cellular functions such as immune response, xenobiotic metabolism, ubiquitin pathway, transcription regulation were affected by HBsAg expression, indicating a close association between HBsAg and host cells. Experiment Overall Design: HBsAg particles are composed of viral envelope proteins and outnumber HBV virions by 1000:1 or even higher. This unique characteristic of HBV remains to be one of the challenges in basic and clinical aspects of viral hepatitis B. Experiment Overall Design: In this study, we want to explore the interactions between HBsAg and hepatocytes, concentrating on the effects of persistently secreting HBsAg on host cell functions.
2008-06-13 | E-GEOD-4549 | biostudies-arrayexpress