RNA Sequencing Facilitates Quantitative Analysis of Humanized Normal Livers, NASH Livers, and HCC Transcriptomes
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE205881 | GEO | 2025/01/01
REPOSITORIES: GEO
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Project description:RNA Sequencing Facilitates Quantitative Analysis of Humanized Normal Livers, NASH Livers, and HCC Transcriptomes
| PRJNA847988 | ENA
Project description:Transgenic mice (n= 40) overexpressing FEAT in the thymus, spleen, liver, and lung developed malignant lymphoma (47.5%, 19/40) and liver cancer (hepatocellular carcinoma, HCC) (35%, 14/40). Notably, HCC arose in half (13/26) of the male transgenic mice, indicating a strong male predilection similar to human HCC. Microarray-based comparative genomic hybridization (array-CGH) suggested that HCC in FEAT transgenic mice recapitulates human hepatocarcinogenesis.
2009-10-15 | GSE18403 | GEO
Project description:To explore functionally crucial tumor-suppressive (TS)-miRNAs in hepatocellular carcinoma (HCC), we performed integrative function- and expression-based screenings of TS-miRNAs in six HCC cell lines. The screenings identified seven miRNAs, which showed growth-suppressive activities through the overexpression of each miRNA and were endogenously downregulated in HCC cell lines. Further expression analyses using a large panel of HCC cell lines and primary tumors demonstrated four miRNAs, miR-101, -195, -378 and -497, as candidate TS-miRNAs frequently silenced in HCCs. Among them, two clustered miRNAs miR-195 and miR-497 showed significant growth-suppressive activity with induction of G1 arrest. Comprehensive exploration of their targets using Argonute2-immunoprecipitation-deep-sequencing (Ago2-IP-seq) and genome-wide expression profiling after their overexpression, successfully identified a set of cell-cycle regulators, including CCNE1, CDC25A, CCND3, CDK4, and BTRC. Our results suggest the molecular pathway regulating cell cycle progression to be integrally altered by downregulation of miR-195 and miR-497 expression, leading to aberrant cell proliferation in hepatocarcinogenesis. Screening of frequently downregulated miRNAs by comparing endgeneous expression status of miRNAs in 6 HCC cell lines with 2 normal livers Expression analysis using total RNAs extracted from standard medium conditioned 6 HCC cell lines, and 2 normal livers derived from patients with hepatectomy due to metastatic liver tumor
2013-05-31 | E-GEOD-41077 | biostudies-arrayexpress
Project description:Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death world-wide. The prevalence of non-alcoholic fatty liver disease (NAFLD) has been rising, along with an increase in NAFLD-related HCC. To investigate cell-type composition in NAFLD and HCC, we performed single-nucleus RNA-seq (snRNA-seq) of patients with fatty liver disease in order to transcriptionally characterize cell-types in an unbiased manner. Out data reveal a large amount of heterogeneity in hepatocyte populations, as well as recovering all expected liver cell-types.
2021-11-23 | GSE189175 | 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:To identify proteomic signatures associated with hepatocellular carcinoma driven by MYC overexpression, proteomics was performed on the LAP-tTA/tetO-MYC mouse conditional liver cancer model. Upon MYC activation, mice form liver cancer. Differential proteomics was performed in "MYC on" (MYC-HCC) mouse liver tumors versus mouse control normal liver tissue (where MYC was not overexpressed to drive tumorigenesis -- "MYC off").
2022-10-12 | PXD031478 | Pride
Project description:In solid tumors, the exhaustion of natural killer (NK) cells and cytotoxic T cells in the immunosuppressive tumor microenvironment poses challenges for effective tumor control. Conventional humanized mouse models of hepatocellular carcinoma-patient-derived xenografts (HCC-PDX) encounter limitations in NK-cell infiltration, hindering studies on NK-cell immunobiology. Here, we introduce an improved humanized mouse model with restored NK-cell reconstitution and infiltration in HCC-PDX, coupled with single-cell RNA-sequencing (scRNA-seq) to identify potential anti-HCC treatments. A single administration of adeno-associated virus carrying human interleukin-15 (AAV-hIL15) reinstated persistent NK-cell reconstitution and infiltration in HCC-PDX in humanized mice. ScRNA-seq revealed exhausted NK-cell and T-cell subpopulations with heightened PDCD1 and TIGIT levels. Notably, combination therapy with anti-PD-1 and anti-TIGIT antibodies alleviated HCC burden in humanized mice, demonstrating NK cell-dependent efficacy. Bulk-RNA sequencing analysis also revealed significant alterations in the tumor transcriptome that may contribute to further resistance after combination therapy, warranting further investigations. As an emerging strategy, ongoing clinical trials with anti-PD-1 and anti-TIGIT antibodies provide limited data. The improved humanized mouse HCC-PDX model not only sheds light on the pivotal role of NK cells but also serves as a robust platform for evaluating safety and anti-tumor efficacy of combination therapies and other potential regimens, complementing clinical insights.
2024-12-28 | GSE265770 | GEO
Project description:Paraffin-embedded paired tumor and peri-carcinoma tissues (n=4) were obtained from the Biorepository of Fudan University Institute of Liver Cancer, which were used for the Affymetrix microarray analysis To investigate the progression of NASH to HCC, we established a differential gene expression profile by analyzing significant expression changes in pathologically confirmed NASH-HCC and peri-carcinoma specimens using Affymetrix microarrays.
2020-06-01 | GSE99807 | GEO
Project description:The circadian clock represents an evolutionarily acquired gene network that synchronizes physiology to anticipate environmental changes caused by the succession of day and night. While most mammalian cells have a circadian clock, their synchronization depends on a central pacemaker located in the suprachiasmatic nuclei (SCN) of the hypothalamus that integrates light signals. While peripheral organs can be also synchronized by feeding cues and can be uncoupled from the central pacemaker, no impact of peripheral organs on the central clock has been yet observed. Here, we used a mouse chimeric model in which mouse hepatocytes have been replaced by human hepatocytes that have different circadian and signaling properties to characterize such potential feedback. Remarkably, we observed that liver humanization rewired the liver diurnal gene expression and advance the circadian clock by approximately 4 hours. Strikingly, this phase advance was also observed in the muscle and for the entire rhythmic physiology of the animals, with an impact of human hepatocytes on the circadian function of the central clock. Like mice with a deficient central clock, the humanized animals shifted their physiology more rapidly to the light phase under day feeding. This data prompt to reconsider the role of peripheral clocks on the central pacemaker and offers new perspective to understand the impact of diseased organs on the global circadian physiology.
2023-05-25 | GSE212079 | GEO
Project description:Hepatocellular carcinoma (HCC) has dismal treatment responses to systemic therapies and is caused by both, viral and non-viral etiologies, including non-alcoholic steatohepatitis (NASH) 1–5. NASH - triggered by high caloric intake and sedentary lifestyle - has become an important driver for HCC development. Immunotherapy has been recently approved for HCC but stratification of responders versus non-responders has remained an unmet need 5–8. Here, we found a progressive accumulation of non-classical activated CD8+PD-1+ T-cells in livers of NASH-affected patients and mice. PD-L1/PD-1-targeted immunotherapy of NASH-induced HCC administered either at cancer-initiation or after cancer-establishment lacked beneficial effects in mice. On the contrary, PD-1-targeted immunotherapy drove hepatic necro-inflammation and increased liver cancer incidence, tumor number, and nodule size. Anti-CD8 or anti-CD8/anti-NK1.1 treatment suppressed liver cancer development, implicating CD8+ T-cells as liver cancer drivers in the context of NASH. In line, PD-1-/- mice challenged with a NASH-inducing diet displayed early-onset of liver cancer. Mechanistically, PD-1-targeted immunotherapy triggered necro-inflammation and a pro-tumorigenic environment in the context of NASH, increasing the abundance of hepatic TOX+CXCR6+ expressing CD8+PD-1+ TNF+ T-cells. Anti-CD8/anti-PD-1 or anti-TNF/anti-PD-1, but not anti-CD4/anti-PD-1 treatment reverted anti-PD1 treatment-related increase of liver inflammation, NASH severity and tumorigenesis. Gene expression profile and increased abundance of murine hepatic CD8+PD-1+ T-cells were corroborated in human CD8+PD-1+ T cells derived from NASH patients. In a meta-analysis of clinical trials testing PD-1-targeting immune checkpoint inhibitors alone (i.e. pembrolizumab) or in combination in 1656 patients with advanced HCC, immunotherapy was not favorable over to control treatment in non-viral- when compared to viral-related HCC. Similarly, in two clinical cohorts tested, patients with NASH-driven HCC had a significantly worse overall survival with PD-1-targeted immunotherapy than HCC patients with other etiologies. Our data identify non-viral etiologies, particularly NASH, as potentially non-responsive in the context of HCC immunotherapy, providing a strong rational basis for patient stratification.
2020-10-24 | GSE159977 | GEO