Functional analysis of antitumor and antiviral effects associated with changes in FAH expression in HBV-stably transfected HepG2 cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE318185 | GEO | 2026/02/04
REPOSITORIES: GEO
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Project description:Functional analysis of antitumor and antiviral effects associated with changes in FAH expression in HBV-stably transfected HepG2 cells
| PRJNA1416874 | ENA
Project description:RNA chemical modifications have been found to play important biological functions. Among which, the 5-methylcytosine (m5C) modification has been reported to participate in viral replication through affecting RNA processing, such as export, decay, translation and so on. In this study, we performed bisulfite sequencing (BS-seq) on HBV 1.1-mer-transfected huh7 cells to identify the m5C sites in HBV mRNA and their function in virus replication was verified. To investigate the mechanism by which m5C methyltransferase NSUN2 suppresses HBV replication, altered global m5C levels in host genes in HBV 1.1-mer-transfected cells were examined by BS-seq. We found that the m5C modification of genes associated with antiviral immunity changed significantly after viral infection. Our study provide new molecular insights into the mechanism of HBV-mediated IFN inhibition
2023-11-07 | GSE246879 | 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: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:Hepatitis B virus (HBV) causes both acute and chronic liver inflammation. Approximately 600,000 CHB patients each year die of HBV-related diseases such as cirrhosis and liver cancer. Therefore, CHB remains a global health concern. Although there have been anti-HBV agents for treating CHB, they have some limitations including viral-drug resistance and adverse effects. Type III IFN or IFN-λ is promising to use as anti-HBV agents because of its anti-viral activities like type I IFNs. In addition, the expression of its receptor, IFNLR1, is limited only in epithelial cells including hepatocytes. Thus, treatment with IFN-lambda results in less side effects compared to IFN-alpha treatment. IFN-lambdas have been shown to inhibit the replication of several viruses including IAV, DENV, EMCV, HIV, HCV, and HBV; however, there have been no studies on the effects of IFN-λ3, the highest activity among other subtypes, on HBV replication. Therefore, this study aims to determine antiviral activities of IFN-λ3 against HBV replication and to investigate its molecular mechanism responsible for suppressing HBV propagation. The results showed that HBV transcripts and amount of intracellular HBV DNA were decreased in HepG2.2.15 cells, stable HBV-transfected hepatoblastoma cell line, treated with IFN-λ3 in a dose-dependent manner. This indicated that IFN-λ3 could inhibit HBV replication. Next, we performed quantitative proteomics to investigate the proteome changes in HepG2.2.15 treated with IFN-λ3. The proteins that changed their expressions were involved in several biological processes such as defense to viral infection, immune responses, cell-cell adhesion, transcription, translation, and metabolism. We further confirmed the proteomics results by immunoblotting assay. Consistent with MS data, it found that the expression of OAS3, SAMHD1 and STAT1 were increased as a result of IFN-λ3 stimulation. These results indicated that proteomics results were reproducible and reliable. Finally, we proposed 3 possible mechanisms involved in suppressing HBV replication including i.) IFN-λ3 induced anti-viral proteins affecting many steps in HBV life cycle ii.) IFN-λ3 promoted antigen processing and antigen presentation and iii.) IFN-λ3 rescued RIG-I signaling to promote both type I and type III IFN production.
2018-08-17 | PXD007896 | Pride
Project description:Reprogramming metabolism plays an important role in tumor cells for maintaining their abnormal biologic behaviors. Therefore, special factors could regulate metabolic processes and influence the overall status of tumor cells. This phenomenon was obviously found in melanoma. Fumarylacetoacetate hydrolase (fumarylacetoacetase, FAH) is an enzyme encoded by the FAH gene located on the chromosome 15q25.1 region and contains 14 exons. FAH enzyme catalyzes the hydrolysis of 4- fumarylacetoacetase into fumarate and acetoacetate. It is the last enzyme in the subpathway from L-phenylalanine and tyrosine degradation. Mutations in the FAH gene cause type I tyrosinemia, which is a hereditary error of metabolism that is characterized by increased tyrosine levels in the blood and urine of patients. In the present study, we will explore whether FAH is an essential enzyme to promote multiple metabolic processes and elucidate the functions of FAH in melanoma. Gene microarrays and bioinformatics analysis of the differentially expressed genes (DEGs) were performed using A375 cells, and we concentrated on the biologic functions of FAH. In general, our work revealed several functional mechanisms of FAH in melanoma, which indicated FAH might be a potentially therapeutic target and an independent prognostic indicator for this disease.
2018-02-14 | GSE86870 | GEO
Project description:Chronic hepatitis B (CHB) is a global health care challenge and a major cause of liver disease. Existing therapies do not result in a functional cure in most individuals, necessitating new antiviral strategies against Hepatitis B virus (HBV). To identify additional therapeutic avenues, we performed a focused screen of epigenetic modifiers to identify inhibitors of HBV replication. From this work we identified small molecule inhibitors of the histone lysine demethylase 5 (KDM5) with antiviral activity against HBV. To enhance the cellular permeability and liver accumulation of the most potent KDM5 inhibitor identified (GS-080) a prodrug was developed (GS-5801) that resulted in improved bioavailability and liver exposure as well as increased accumulation of the H3K4me3:H3 ratio on chromatin. GS-5801 treatment of HBV-infected primary human hepatocytes inhibited HBV replication and antigen levels. Evaluation of GS 5801 antiviral activity in a humanized mouse model of HBV infection, however, did not result in antiviral efficacy, despite achieving pharmacodynamic levels of H3K4me3:H3 predicted to be efficacious. Together these data highlight discordance between the antiviral effects of GS 5801 observed in rodent livers.
2021-02-24 | GSE166040 | GEO
Project description:Chronic hepatitis B (CHB) is a global health care challenge and a major cause of liver disease. Existing therapies do not result in a functional cure in most individuals, necessitating new antiviral strategies against Hepatitis B virus (HBV). To identify additional therapeutic avenues, we performed a focused screen of epigenetic modifiers to identify inhibitors of HBV replication. From this work we identified small molecule inhibitors of the histone lysine demethylase 5 (KDM5) with antiviral activity against HBV. To enhance the cellular permeability and liver accumulation of the most potent KDM5 inhibitor identified (GS-080) a prodrug was developed (GS-5801) that resulted in improved bioavailability and liver exposure as well as increased accumulation of the H3K4me3:H3 ratio on chromatin. GS-5801 treatment of HBV-infected primary human hepatocytes inhibited HBV replication and antigen levels. Evaluation of GS 5801 antiviral activity in a humanized mouse model of HBV infection, however, did not result in antiviral efficacy, despite achieving pharmacodynamic levels of H3K4me3:H3 predicted to be efficacious. Together these data highlight discordance between the antiviral effects of GS 5801 observed in HBV-infected primary human hepatocytes.
2021-02-24 | GSE165727 | GEO
Project description:Background and Aims: Whether hepatitis B virus (HBV) could play a direct role in hepatocarcinogenesis remains uncertain. The 3' end nonsense mutations of HBV PreS/S gene have been found to encode transcriptional transactivation activity, suggesting these mutations may contribute to HBV-associated oncogenesis. Recently, we have identified a potent oncogenic HBV surface (S) gene nonsense mutant sW182*. Results: Gene expression microarray study revealed that sW182* mutant was significantly enriched by gene sets associated with cell cycle regulation, DNA repair, or genome instability. The transforming growth factor-induced (TGFBI) gene was downregulated in the sW182* mutant clones, and irresponsive to TGF- treatment. The level of Cyclin D1, a negatively regulated TGFBI target, was highly elevated in sW182* mutant cells. Exogenous expression of TGFBI alleviated the oncogenic activity of sW182* in mouse xenograft study. In human HBV-related HCC cancerous tissue, expression of TGFBI was downregulated in 25 of the 55 (45%) patients. Conclusions: Dysregulation of transforming growth factor-induced (TGFBI) gene is involved in the oncogenic activity of the sW182* mutant of hepatitis B virus S gene. This has never been described before. NIH3T3 cells were stably transfected with plasmids encoding the wild type PreS/S gene or the nonsense mutant (sW182*) of HBV PreS/S gene. Totoal RNAs were extracted from those stable clones for gene expression microarray analysis using Illumina MouseRef-8 V2 BeadChip.
2014-07-30 | E-GEOD-50180 | biostudies-arrayexpress
Project description:Background and Aims: Whether hepatitis B virus (HBV) could play a direct role in hepatocarcinogenesis remains uncertain. The 3' end nonsense mutations of HBV PreS/S gene have been found to encode transcriptional transactivation activity, suggesting these mutations may contribute to HBV-associated oncogenesis. Recently, we have identified a potent oncogenic HBV surface (S) gene nonsense mutant sW182*. Results: Gene expression microarray study revealed that sW182* mutant was significantly enriched by gene sets associated with cell cycle regulation, DNA repair, or genome instability. The transforming growth factor-induced (TGFBI) gene was downregulated in the sW182* mutant clones, and irresponsive to TGF- treatment. The level of Cyclin D1, a negatively regulated TGFBI target, was highly elevated in sW182* mutant cells. Exogenous expression of TGFBI alleviated the oncogenic activity of sW182* in mouse xenograft study. In human HBV-related HCC cancerous tissue, expression of TGFBI was downregulated in 25 of the 55 (45%) patients. Conclusions: Dysregulation of transforming growth factor-induced (TGFBI) gene is involved in the oncogenic activity of the sW182* mutant of hepatitis B virus S gene. This has never been described before.
2014-07-30 | GSE50180 | GEO