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The main Transcription factor of Notch signalling RBPJ inhibits the formation of combined HCC-iCCA

ABSTRACT: Background & Aims: Combined HCC-iCCA is a rare liver tumor type and is often not well separated from HCC and iCCA. In this study, we analyzed major differences between combined HCC-iCCA and iCCA. Methods: We first characterized major differences between combined HCC-iCCA and iCCA by GSEA analysis. Consequently, we used CCl4 to induce chronic liver disease and subsequent liver carcinoma formation in mice. We forced the formation of combined HCC-iCCA through liver specific deletion of Rbpj, a key component of the Notch signaling pathway, in a Trp53 deficient background. Notch and p53 signaling pathways are involved in cellular differentiation processes and belong to the most affected pathways in liver carcinogenesis. Results: We show that combined HCC-iCCA can be separated from iCCA through differences in development related pathways, metabolism, cell to cell interaction and immune related pathways in human patients and in mice. Dysregulation of Notch signaling through a hepatocyte-specific Rbpj knockout resulted in an increased tumor burden and a high frequency of combined HCC-iCCA formation. In addition, hepatocytic loss of Rbpj forced M2 macrophage polarization and a tumor promoting environment. Conclusions: Dysregulation of Notch signaling is involved in tumor differentiation. Loss of Rbpj triggers the formation of combined HCC-iCCA which is associated by a pro-tumorigenic environment. Our study highlights the importance of dysfunctional Notch signalling through Rbpj deletion in hepatocytes. Rbpj loss affects tumor differentiation and the tumor microenvironment which can be linked to a combined HCC-iCCA phenotype seen in human patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE212095 | GEO | 2023/08/31

REPOSITORIES: GEO

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Bilineal differentiated liver carcinoma cells generates highly aggressive escape variants

Project description:Background & Aims: Combined HCC/iCCA is a rare liver tumor type. We generated a transgenic mouse model (AlfpCre+-Trp53fl/fl/Alb-HBs+ tg mouse) which developed next to HCC combined HCC/iCCA (cHCC/iCCA). We compared bilineal differentiated liver carcinoma cell lines generated from primary liver tumors of AlfpCre+-Trp53fl/fl/Alb-HBs+ tg mice and transplanted them into C57BL/6J mice to monitor there agressiveness. We compared the geneexpression profile from those primary liver carcinoma cell lines with IFNγ treatment (pCCL-IFNγ) and without treatment (pCCL) with explanted primary carcinoma cell line (pCCL-ex). Results: Here we describe that elimination of HBs+ in pCCL by HBs/(Kb/S190-197)-specific CD8 T cells describes a potential immune escape mechanism for highly aggressive cHCC/iCCA-type liver carcinomas.

2023-05-23 | GSE215059 | GEO

Effect of NOTCH-γ-secretase inhibitor LY3039478 therapy on patient derived xenograft (PDX) mouse model of intrahepatic cholangiocarcinoma

Project description:Intrahepatic Cholangiocarcinoma (iCCA) is a deadly disease with rising incidence and few treatment options. Recently, aberrant Notch signaling was reported in iCCA carcinogenesis. Specifically, altered expression and/or activation of the receptors Notch1/2 suggests a role for Notch pathway overactivation during iCCA formation and progression. In this study, we examined the effects of Notch inhibition by γ-secretase inhibitor, LY3039478 in human iCCA cell lines and in an excellent patient derived-xenograft (PDX) model. Expression of several Notch pathway components, including NICD, Hes1, and DLL4, were reduced after GSI treatment. Moreover, LY3039478 inhibits cell migration and invasion while in GSI-treated mice, tumor growth was delayed compared to vehicle and chemotherapy. These results support the notion that Notch inhibition by GSI may reduce in vivo tumorigenesis. In addition, GSI reduces in PDX model VEGFA and MMP13 involved in capillary tube formation and tumor progression. Here, we therefore show a link between the efficacy of Notch inhibition and the tumor microenvironment through LY3039478 that slows tumor progression compared to control mice blocking angiogenesis via MMP13 downregulation. We used microarray technology to understand the molecular mechanisms affected by LY3039478. Cholangiocarcinoma PDX model was employed in this analysis.

2020-07-27 | GSE134114 | GEO

Liver regeneration after cholestatic damage induced by Rbpj deletion

Project description:Liver cholestasis is a chronic liver disease (CLD) which belongs to a major health problem. Cholestasis is characterised by a decrease in bile flow due to impaired secretion by hepatocytes or by obstruction of bile flow through intra- or extrahepatic bile ducts. Thereby cholestasis can induce ductal proliferation, hepatocyte injury and liver fibrosis. Notch signalling promotes the formation and maturation of ductular reactions. We investigated the liver regeneration process in the context of cholestasis induced by disruption of the Notch signalling pathway. Liver-specific deletion of Rbpj, which represents a key regulator of Notch signalling, induces severe cholestasis through impaired IHBD maturation, severe necrosis and increased lethality. Deregulation of the biliary compartment and cholestasis are associated with change of several signalling pathways including the Hippo pathway resulting in upregulation of SOX9, which is associated with transdifferentiation of hepatocytes. SOX9 upregulation in cholestatic liver injury in vitro is independent of Notch signalling. We could comprehensively address that Rbpj depletion is followed by deregulation of YAP/TEAD, which influences transdifferentiation of hepatocytes and thereby contributing to liver regeneration. In this study the liver regeneration process was analyzed in 4 weeks old Rbpj knockout mice and compared to 4 weeks old Rbpj wildtype mice.

2018-10-17 | GSE121302 | GEO

RBPJ/CBF1 interacts with L3MBTL3/MBT1 to promote repression of Notch signaling via histone demethylase KDM1A/LSD1

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2017-10-17 | PXD004196 | Pride

RNA-seq Profiles in RBPJ Maintains Brain Tumor Initiating Cells through CDK9-mediated Transcriptional Elongation

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2016-05-01 | GSE79735 | GEO

Molecular and radiopathologic spectrum between HCC and intrahepatic cholangiocarcinoma

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2022-07-12 | GSE179443 | GEO

RNA-sequence data of liver sinusoidal endothelial cells from control and endothelial RBPj-deficent mice with liver fibrosis

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2020-04-01 | GSE120282 | GEO

H014: HES5 mediates NOTCH signaling by interaction with AKT to drive liver carcinogenesis

Project description:Notch signaling plays a pivotal role in liver development and aberrant Notch signaling may lead to hepatocellular (HCC) or cholangiocellular carcinoma (CCA) development. Using whole exome sequencing of 54 human HCC samples, we discovered 19 somatic missense mutations in 15 different Notch pathway genes affecting 24.6% (14 of 57) of patients. Prediction of functional impact of these Notch pathway mutations revealed HES5-R31G to have high relevance. We found HES5 to be strongly activated by Notch signaling. In vitro, HES5 reduced cell migration and clonogenicity and in vivo, HES5 inhibited MYC-dependent liver tumor formation. But together with AKT, HES5 increased liver tumor formation in a mouse model. HES5 directly binds to AKT and AKT expression leads to increase HES5 protein levels. Furthermore, HES5 exhibits a negative feed-back loop by inhibiting NOTCH1 and HES1 gene expression. In contrast, HES5-R31G appears to be non-functional possibly by loss of nuclear translocation

| EGAS00001003329 | EGA

FBXO42 facilitates Notch signaling activation and global chromatin relaxation by promoting K63-linked polyubiquitination of RBPJ

Project description:Dysregulation of the Notch-RBPJ signaling pathway has been found associated with various human diseases including cancers; however, precisely how this key signaling pathway is fine-tuned via its interactors and modifications is still largely unknown. In this study, using a proteomic approach, we identified FBXO42 as a novel RBPJ interactor. FBXO42 promotes RBPJ polyubiquitination on lysine (K) 175 via K63 linkage, which enhances the association of RBPJ with chromatin remodeling complexes and induces a global chromatin relaxation. Genetically depleting FBXO42 or pharmacologically targeting its E3 ligase activity attenuates the Notch signaling-related leukemia development in vivo. Taken together, our findings not only revealed FBXO42 as a critical regulator of the Notch pathway by modulating RBPJ-dependent global chromatin landscape changes, but also provide insights into the therapeutic intervention of the Notch pathway for leukemia treatment.

2022-10-13 | PXD034938 | Pride

Activation of a neural stem cell transcriptional program in parenchymal astrocytes

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2020-08-01 | E-MTAB-9268 | biostudies-arrayexpress

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