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GPNMB+Gal-3+ Hepatic Parenchymal Cells Promote Immunosuppressive Microenvironment Formation and Hepatocellular Carcinogenesis

ABSTRACT: Hepatocellular carcinoma (HCC) involves a multistep pathological process in which heterogenous cells are evolved to shape an immunosuppressive microenvironment. Yet it remains largely unknown regarding the specific cell populations and their evolving routes essential for HCC development. Here, we created a rat model mimicking human HCC and generated a single-cell resolution atlas to HCC development. Specifically, we identified three populations of hepatic parenchymal cells during HCC progression, i.e., metabolic hepatocyte (HC Meta ), hepatic progenitor cell-like population with differentiation potential (HPC-like Diff ) and immunosuppressive malignant transformation subset (H-M Immu ). These three distinct subpopulations formed an oncogenic trajectory depicting a dynamic landscape of hepatocyte carcinogenesis, with signature genes reflecting the transition from HPC-like Diff to H-M Immu . Cross-species comparative analysis further revealed the H-M Immu subset to be highly conserved. Importantly, the H-M Immu (GPNMB + Gal-3 + ) cells exhibit both malignant and immunosuppressive properties. Moreover, SOX18 was found to be required for the generation of GPNMB + Gal-3 + H-M Immu cells and for their ability to form tumors. Enrichment of GPNMB + Gal-3 + H-M Immu subset was found to be associated with poor prognosis and higher rate of recurrence for HCC patients. Collectively, we unraveled the single-cell evolving mechanism of HCC and uncovered GPNMB + Gal-3 + H-M Immu cells as a major subset contributing to the immunosuppressive microenvironment and HCC malignance

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE218561 | GEO | 2023/08/10

REPOSITORIES: GEO

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GPNMB+Gal-3+ Hepatic Parenchymal Cells Promote Immunosuppressive Microenvironment Formation and Hepatocellular Carcinogenesis.

Project description:Hepatocellular carcinoma (HCC) involves a multistep pathological process in which heterogenous cells are evolved to shape an immunosuppressive microenvironment. Yet it remains largely unknown regarding the specific cell populations and their evolving routes essential for HCC development. Here, we created a rat model mimicking human HCC and generated a single-cell resolution atlas to HCC development. Specifically, we identified three populations of hepatic parenchymal cells during HCC progression, i.e., metabolic hepatocyte (HC Meta ), hepatic progenitor cell-like population with differentiation potential (HPC-like Diff ) and immunosuppressive malignant transformation subset (H-M Immu ). These three distinct subpopulations formed an oncogenic trajectory depicting a dynamic landscape of hepatocyte carcinogenesis, with signature genes reflecting the transition from HPC-like Diff to H-M Immu . Cross-species comparative analysis further revealed the H-M Immu subset to be highly conserved. Importantly, the H-M Immu (GPNMB + Gal-3 + ) cells exhibit both malignant and immunosuppressive properties. Moreover, SOX18 was found to be required for the generation of GPNMB + Gal-3 + H-M Immu cells and for their ability to form tumors. Enrichment of GPNMB + Gal-3 + H-M Immu subset was found to be associated with poor prognosis and higher rate of recurrence for HCC patients. Collectively, we unraveled the single-cell evolving mechanism of HCC and uncovered GPNMB + Gal-3 + H-M Immu cells as a major subset contributing to the immunosuppressive microenvironment and HCC malignance

2024-01-02 | GSE243688 | GEO

GPNMB+Gal-3+ Hepatic Parenchymal Cells Promote Immunosuppressive Microenvironment Formation and Hepatocellular Carcinogenesis

Project description:GPNMB+Gal-3+ Hepatic Parenchymal Cells Promote Immunosuppressive Microenvironment Formation and Hepatocellular Carcinogenesis

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GPNMB+Gal-3+ Hepatic Parenchymal Cells Promote Immunosuppressive Microenvironment Formation and Hepatocellular Carcinogenesis.

Project description:GPNMB+Gal-3+ Hepatic Parenchymal Cells Promote Immunosuppressive Microenvironment Formation and Hepatocellular Carcinogenesis.

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Cell-permeated peptide P-T3H2 inhibits malignancy on hepatocarcinoma through stabilizing HNF4α protein

Project description:Objectives: Hepatocyte nuclear factor 4α (HNF4α) is a key regulator of hepatocyte function and has a strong therapeutic effect on hepatocellular carcinoma (HCC) by inducing the differentiation of hepatoma cell into hepatocytes. Our previous study showed that Tribbles homolog 3 (TRIB3) directly interacts with and promotes the degradation of HNF4α in non-alcoholic fatty liver disease (NAFLD). Disrupting the TRIB3-HNF4α interaction by using a cell-permeating peptide called P-T3H2 stabilizes HNF4α protein. This study aimed to assess the anti-tumor impact of P-T3H2 in HCC. Methods: The expression of TRIB3 and HNF4α was assessed using western blot and immunohistochemistry staining (IHC). Hepatic functions in HCC cells were evaluated through periodic acid-Schiff (PAS) staining and acetylated low-density lipoprotein (ac-LDL) uptake. Senescence-associated β-galactosidase (SA-β-gal) activity staining was used to detected the cellular senescence in HCC cells. RNA-Seq analysis was carried out to identify differentially expressed genes in Huh-7 cells treated with the peptide P-T3H2 compared to the control peptide P-T3H2-2A. The impact of P-T3H2 on hepatocarcinoma malignancy was evaluated in HCC cells, a Huh-7 xenograft mouse model, an orthotopic model, and a C-MET/ΔN90-β-catenin-driven HCC model. Results: TRIB3 exhibited a negative correlation with HNF4α in both human and mouse HCC tissues. The administration of P-T3H2 significantly inhibited the malignancy of HCC cells. Additionally, P-T3H2 stabilized the HNF4α protein and facilitated the restoration of hepatic functions and the cellular senescence in HCC cells. RNA-Seq analysis demonstrated that P-T3H2 enhanced the transcriptional activity of HNF4α in HCC. Furthermore, P-T3H2 effectively suppressed the growth of HCC tumors in both of the Huh7 xenograft and orthotopic mouse models in vivo. Notably, P-T3H2 also inhibits hepatocarcinogenesis in the C-MET/ΔN90-β-catenin-driven HCC model.

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2023-03-11 | PXD026822 | Pride

Tid1 Deficiency Disrupting Mitochondria to Drive NASH-Dependent Hepatocellular Carcinoma Progression

Project description:Non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is a significant risk factor for hepatocellular carcinoma (HCC). However, a preclinical model of progressive NAFLD/NASH is largely lacking. Here, we report that mice with hepatocyte-specific deletion of Tid1, encoding a mitochondrial cochaperone, tended to develop NASH-dependent HCC. Mice with hepatic Tid1 deficiency showed impairing mitochondrial function and causing fatty acid metabolic dysregulation; meanwhile, sequentially developed fatty liver, NASH, and cirrhosis/HCC in a diethylnitrosamine (DEN) induced oxidative environment. The pathological signatures of human NASH, including cholesterol accumulation and activation of inflammatory and apoptotic signaling pathways, are also present in these mice. Clinically, low Tid1 expression was associated with unfavorable prognosis in patients with HCC. Empirically, hepatic Tid1 deficiency directly disrupts entire mitochondria that play a key role in the NASH-dependent HCC development. Overall, we established a new mouse model that develops NASH-dependent HCC and provides a promising approach to improve the treatment.

2022-06-02 | E-MTAB-9973 | biostudies-arrayexpress

An imbalance of tumour-suppressing and tumour-promoting hepatic stellate cell populations in liver fibrosis contributes to hepatocarcinogenesis

Project description:Hepatocellular carcinoma (HCC) develops almost exclusively in patients with chronic liver disease (CLD) and advanced fibrosis. Here we interrogated functions of hepatic stellate cells (HSC), the main source of fibroblasts in the injured liver, during hepatocarcinogenesis. Genetic depletion, activation, or inhibition established HSC as tumour-promoting in different HCC models. HSC were enriched in the non-tumour environment, where they closely interacted with hepatocytes and modulated hepatocarcinogenesis by regulating hepatocyte proliferation and death. Surprisingly, further analysis of mouse and human HSC subpopulations by single cell and single nucleus RNA-sequencing and their associated mediators revealed dual functions of HSC in hepatocarcinogenesis. Hepatocyte growth factor, enriched in quiescent and cytokine-producing HSC (cyHSC), protected from hepatocyte death and HCC development. In contrast, type I collagen, enriched in highly activated myofibroblastic HSC (myHSC), increased stiffness, TAZ activation, and subsequent hepatocyte proliferation, thereby promoting HCC development. An increasing HSC imbalance with decreased protective cyHSC and increased myHSC during liver disease progression was associated with elevated HCC risk in patients. In summary, our data suggest that the dynamic shift of HSC subpopulations during CLD and their mediators is associated with a switch from HCC protection to HCC promotion.

2022-05-01 | GSE174748 | GEO

Comparative gene expression profiling in livers of A1cf-transgenic, A1cf-knockout, and wild-type mice

Project description:Rationale: RNA binding protein Apobec1 Complementation Factor (A1CF) regulates posttranscriptional ApoB mRNA editing but the range of RNA targets and long-term impact of altered A1CF expression on liver function are unknown. Objective: We studied hepatocyte-specific A1cf transgenic (A1cf +/Tg), A1cf+/Tg Apobec1– /– and A1cf –/– mice fed chow or high fat/high fructose diets using RNA-Seq, RNA-CLIP Seq and tissue microarrays from human hepatocellular cancer (HCC). Findings: A1cf +/Tg mice exhibited increased hepatic proliferation and steatosis, with increased lipogenic gene expression (Mogat1, Mogat2, Cidea, Cd36) associated with shifts in polysomal RNA distribution. Aged A1cf +/Tg mice developed spontaneous fibrosis, dysplasia and HCC, which was accelerated on a high fat/fructose diet and independent of Apobec1. RNA-Seq revealed increased expression of mRNAs involved in oxidative stress (Gstm3, Gpx3, Cbr3), inflammatory response (Il19, Cxcl14, Tnfα, Ly6c), extracellular matrix organization (Mmp2, Col1a1, Col4a1), proliferation (Kif20a, Mcm2, Mcm4, Mcm6) with a subset of mRNAs (including Sox4, Sox9, Cdh1) identified in RNA CLIP-Seq. Increased A1CF expression in human HCC correlated with advanced fibrosis and with reduced survival in a subset with nonalcoholic fatty liver disease. Conclusions: Hepatic A1CF overexpression selectively alters polysomal distribution and mRNA expression, promoting lipogenic, proliferative and inflammatory pathways leading to HCC.

2020-09-01 | GSE157233 | GEO

Comparative gene expression profiling in livers of A1cf-transgenic and wild-type mice

2020-09-05 | GSE157516 | GEO

Gene expression data from acetaminophen-induced toxicity in human hepatic in vitro systems and clinical liver samples

Project description:In this study we conducted transcriptomics analyses of: (i) liver samples from patients suffering from acetaminophen-induced acute liver failure (n=3) and from healthy livers (n=2) and (ii) hepatic cell systems exposed to acetaminophen, including their respective vehicle controls. The investigated in vitro systems are: HepaRG cells, HepG2 cells and a novel human skinpostnatal stem cell-derived model i.e. human skin-precursors-derived hepatocyte-like cells (hSKP-HPC). Clinical samples were obtained after surgical removal of the explant liver of patients diagnosed with ALF due to acetaminophen intoxication and treated by orthotopic liver transplantation (n=3). Samples from healthy livers were obtained from individuals deceased from brain damage (n=2). Different samples of hSKP, HepG2 and HepaRG were obtained from the same cell batch of each cell system. All cells were exposed for 24 hours to their corresponding sub cytotoxic concentrations (IC10): IC10(hSKP-HPC)=18mM; IC10(HepaRG)=13mM; IC10(HepG2)=2mM. Experiments were conducted in triplicate. This dataset is part of the TransQST collection.

2015-11-04 | E-GEOD-74000 | biostudies-arrayexpress

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