Identification of FAD subtypes in mouse HCC models
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ABSTRACT:
PROVIDER: PRJNA834137 | ENA |
REPOSITORIES: ENA
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Project description:In this study, we identified and validated a molecular classification of hepatocellular carcinoma (HCC) based on 42 fatty acid degradation (FAD) genes in clinical samples. We further searched PubMed for the RNA sequencing datasets of mouse models to identify the FAD subtypes in mouse HCC models. A total of 90 samples were collected from five publicly available datasets including 11 mouse HCC models. In addition, the transcriptome sequencing data of 8 samples from our two mouse models (NRAS.MYC.ND and AKT1.MYC.KD) were also included. This dataset aims to explore the transcriptomic characteristics of these two models.
2023-05-01 | GSE202070 | GEO
Project description:In this study, we identified and validated a molecular classification of hepatocellular carcinoma (HCC) patients based on 42 fatty acid degradation (FAD) genes. The F1 subtype was characterized by the lowest expression of FAD genes, whereas F3 subtype had the highest expression levels, and F2 had the intermediate expression levels of FAD genes. We characterized the immune microenvironment in HCC patients from different FAD subtypes. To further explore the immune landscape of HCC, we generated the Nras-driven HCC model (belonging to the F1 subtype) and the Akt1-driven HCC model (belonging to the F3 subtype) by hydrodynamic tail vein injection (HTVi) of oncogenes together with the sleeping beauty transposase. The tumor tissues were resected from the liver 14 weeks after the hydrodynamic delivery of the plasmids, isolated for single cells, and prepared for scRNA-seq.
2023-05-01 | GSE202071 | GEO
Project description:Identification of 5'isomiR in HCC patients.
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Project description:Evaluating pre-clinical models for studying NASH driven HCC.
| PRJNA474086 | ENA
Project description:RNA viruses have developed elaborate strategies for 5’ capping and protection of their genomes. However, so far no 5’ RNA cap has been identified for Hepatitis C virus (HCV), which cause chronic infection, liver cirrhosis and cancer in humans4. Here, we demonstrate that the cellular metabolite flavin adenine dinucleotide (FAD) is used as noncanonical initiating nucleotide by the viral RNA-dependent RNA polymerase resulting in a 5’ FAD cap on the HCV RNA. FAD capping is completely conserved for the HCV replication intermediate negative RNA strand and partially for the positive RNA strand. The prototype strain J6/JFH1 RNA is FAD capped when isolated from the liver and serum of a human liver chimeric mouse model and in vitro the FAD capping frequency is ~75 %, which is the highest metabolite RNA capping frequency observed. Furthermore, we show that 5’ FAD capping protects RNA from cell-intrinsic innate immune recognition but has limited effect on HCV RNA stability. These results establish capping with cellular metabolites, such as FAD, as a novel viral RNA capping and immune evasion strategy, which potentially could be used by many viruses for protection of their intermediate RNA strands and thereby affect viral treatment outcomes and persistency.
2022-07-31 | GSE180956 | GEO
Project description:Riboflavin (RF) and its cofactors (FMN and FAD) are essential molecules for vital metabolic processes in all organisms. Thus, the flavin metabolism must be tightly regulated in the cells. We previously demonstrated that the intracellular levels of flavins were tightly maintained by the enzymes involved in their synthesis and degradation, inducing a plastidic FAD hydrolase (AtNUDX23), in Arabidopsis. However, information of regulatory factors involved in the flavin homeostasis and transporters in each organelle are mostly limited. Terefore, we tried to identify novel factors involved in the flavin metabolism, such as transcription factors and transporters by a transcriptome analysis after exogenous FAD treatment.
2021-03-18 | GSE169061 | GEO
Project description:Two groupsHepatocellular carcinoma (HCC) is a heterogeneous malignant disease with molecularly and clinically distinct subtypes discovered in genomic studies. Mouse models are commonly used as preclinical model to study hepatocarcinogenesis, but how well these models recapitulate molecular subtypes of human HCC is unclear. Thus, we aimed to correlate nine mouse HCC models with clinical subtypes of human HCC by systematically comparing their genomic data. By integrating nine molecularly and clinically defined genomic signatures for human HCC with genomic data from nine mouse HCC models, we identified the mouse models that best resembled subtypes of human HCC and determined the clinical relevance of each model. Mst1/2 KO, Sav1 KO, and SV40 T antigen mouse model best recapitulated poor prognostic subtypes of human HCC, whereas the Myc transgenic model best resembled human HCCs with more favorable prognoses. The Myc model was also significantly associated with activation of β-catenin. E2f1, E2f1/Myc, E2f1/Tgfa, and diethylnitrosamine (DENA)-induced models were heterogeneous and were unequally split to poor and favorable prognoses. Most interestingly, Mst1/2 KO and Sav1 KO models best resembles human HCC with hepatic stem cell characteristics. When we applied a genomic predictor for immunotherapy, the six-gene interferon-γ (IFNG6) score, Mst1/2 KO, Sav1 KO, SV40, and DEN models were predicted to be the least responsive to immunotherapy. Further analysis of immune checkpoint genes showed that high expression of immune inhibitory genes (Cd276 and Pvrl2) in Mst1/2 KO, Sav1 KO, SV40 and low expression of immune stimulatory genes (Cd86) in DENA model might be accountable for lack of predictive response to immunotherapy. Conclusion: Most of the mouse models effectively recapitulated molecular characteristics of human subtypes, including response to immunotherapy. of samples are included: 1.SKOV3-ip1 2.SKOV3-OM3. Gene expression profiles of SKOV3-OM3 cells were compared to that of parental SKOV3 ip1 cells.
2019-01-01 | GSE110627 | GEO
Project description:Background & Aims: Aberrant activation of fatty acid synthase (FASN) is a major metabolic event during the development of HCC. We evaluated the therapeutic efficacy of TVB3664, a novel FASN inhibitor, either alone or in combination, for HCC treatment. Approach & Results: The therapeutic efficacy and the molecular pathways targeted by TVB3664, either alone or with tyrosine kinase inhibitors or the checkpoint inhibitor anti-PD-L1 antibody, were assessed in human HCC cell lines and multiple oncogene-driven HCC mouse models. RNAseq was performed to characterize the global gene expression and metabolic profiles. TVB3664 effectively ameliorated the fatty liver phenotype in the aged mice and AKT activation-induced hepatic steatosis. TVB3664 monotherapy showed moderate efficacy in NASH-related murine HCCs, induced by loss of PTEN and c-MET overexpression. TVB3664, in combination with cabozantinib, triggered tumor regression in this mouse HCC model but did not improve the responsiveness to immunotherapy. Global gene expression revealed that TVB3664 predominantly modulated metabolic processes, while TVB3664 synergized with cabozantinib to downregulate multiple cancer-related pathways, especially the AKT/mTOR pathway and cell proliferation genes. TVB3664 also improved the therapeutic efficacy of sorafenib and cabozantinib in the FASN-dependent c-MYC HCC model. However, TVB3664 had no efficacy nor synergistic effects in FASN-independent mouse HCC models. Conclusions: This preclinical study suggests the limited efficacy of targeting FASN as monotherapy for HCC treatment. However, FASN inhibitors could be combined with other drugs for improved effectiveness. These combination therapies could be developed based on the driver oncogenes, supporting precision medicine approaches for HCC treatment.
2022-01-28 | GSE189529 | GEO
Project description:Therapeutic efficacy of FASN inhibition in preclinical models of HCC
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Project description:Pseudomonas sp. ZH-FAD Genome sequencing and assembly
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