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NOTCH/HES5 signaling exhibits distinct roles in MYC- and AKT-driven liver carcinogenesis

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE121362 | GEO | 2019/10/31

REPOSITORIES: GEO

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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

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NOTCH/HES5 signaling exhibits distinct roles in MYC- and AKT-driven liver carcinogenesis

Project description:NOTCH/HES5 signaling exhibits distinct roles in MYC- and AKT-driven liver carcinogenesis

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Transient Hes5 activity instructs mesodermal cells toward a cardiac fate

Project description:Notch signaling plays a role in specifying a cardiac fate but the downstream effectors remain unknown. In this study we implicate the Notch downstream effector HES5 in cardiogenesis. We show transient Hes5 expression in early mesoderm of gastrulating embryos and demonstrate, by loss and gain-of-function experiments in mouse embryonic stem cells, that HES5 favors cardiac over primitive erythroid fate. Hes5 overexpression promotes upregulation of the cardiac gene Isl1, while the hematopoietic regulator Scl is downregulated. Moreover, whereas a pulse of Hes5 instructs cardiac commitment, sustained expression after lineage specification impairs progression of differentiation to contracting cardiomyocytes. These findings establish a role for HES5 in cardiogenesis and provide insights into the early cardiac molecular network.

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Mixed hepatocellular – cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL6 trans-signaling, single-cell RNA sequencing

Project description:Mixed hepatocellular – cholangiocarcinoma (HCC-CCA) is a highly malignant primary liver cancer of increasing incidence for which the cell of origin and molecular pathogenesis have not yet been fully elucidated. Here, by linking YFP to the progenitor cell specific promoter of Foxl1 in Mdr2-KO mice, we generated a lineage tracing mouse model for liver cancer to monitor the development of mixed HCC-CCA tumors following a prolonged period of liver inflammation. In this model of chronic hepatitis, we demonstrate that liver progenitor cells are the source of mixed HCC-CCA tumors but not of hepatocellular carcinoma (HCC). Moreover, we show that IL6, originating from senescent hepatic cells, is involved in progenitor cell proliferation and development of mixed HCC-CCA tumors via IL6 trans-signaling. These findings could form the basis for the development of novel therapeutic approaches for treatment of mixed HCC-CCA liver cancer.

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Mixed hepatocellular – cholangiocarcinoma derives from liver progenitor cells and depends on senescence and IL6 trans-signaling, bulk RNA sequencing

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Gene expression data of human hepatocellular carcinoma (HCC) and Cholangiocarcinoma (CCA) from Thailand Initiative in Genomics and Expression Research for Liver Cancer (TIGER-LC)

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Copy Number Variation of human hepatocellular carcinoma (HCC) and Cholangiocarcinoma (CCA) from the Thailand Initiative in Genomics and Expression Research for Liver Cancer (TIGER-LC)

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Analyzing human neural stem cell ontogeny by consecutive isolation of Notch active neural progenitors

Project description:Decoding heterogeneity of pluripotent stem cell (PSC)-derived neural progeny is fundamental for revealing the origin of diverse progenitors, for defining their lineages, and for identifying fate determinants driving transition through distinct potencies. Here we prospectively isolated consecutively appearing PSC-derived primary progenitors based on their Notch activation state. We first isolate early neuroepithelial cells and show their broad Notch-dependent developmental and proliferative potential. Neuroepithelial cells further yield successive Notch-dependent functional primary progenitors, from early and mid neurogenic radial glia and their derived basal progenitors, to gliogenic radial glia and adult-like neural progenitors, together recapitulating hallmarks of neural stem cell (NSC) ontogeny. Gene expression profiling reveals dynamic stage specific transcriptional patterns that may link development of distinct progenitor identities through Notch activation. Our observations provide a platform for characterization and manipulation of distinct progenitor cell types amenable for developing streamlined neural lineage specification paradigms for modeling development in health and disease. Human embryonic stem cells (hESCs) H9 were differentiated into 5 distinct populations of neural precursor cells (NPCs) over a time course of 200 days. Each neural precursor populations was then sorted for HES5 expression based on a GFP-HES5 reporter. Both the HES5 positive and HES5 negative populations were then subjected to microarray profiling in singlicate, as well as the hESCs using GeneChipPrimeView Human Gene Expression Array

2015-02-18 | E-GEOD-65369 | biostudies-arrayexpress

Epigenetic landscapes in wild-type and dimer-mutant Notch regulated T-LL cells

Project description:NOTCH/RBPJ/MAML ternary transcriptional complex binds to regulatory element and drives gene expression. The complex can function as monomer and dimer. How dimeric complexes regulate gene expression in human cancer is not well studied. Here, we integrate genomic data sets and analyze Notch dimeric complexes-regulated transcriptome and cis-regulatory elements. A subset of coding and non-coding RNA is Notch dimeric complexes-associated. Dimeric complexes recognition sequence enriched in functional dynamic Notch sites and majority of dimer recognition sequence located in (super-)enhancers. Using CRISPR-Cas9-mediated genome editing, we evaluated the function of one dimer-responsive element located in the promoter region of a noncoding RNA NDANR1 and 5' end 16kb away from HES5. Mutation of SPS in this element reduced expression of HES5 and NDANR1. This finding indicates that dimer-responsive elements can function as enhancer for HES5 and at the same time can function as promoter for noncoding RNA NDANR1. Our study reveals the pervasive role of Notch dimeric complexes in transcriptional regulation in human cancer genome.

2017-08-23 | GSE72175 | GEO

Transcriptomic profiling of the intermediate cell carcinoma of the primary liver cancer

Project description:Introduction: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a mixed-type tumor of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), which is classified into classical type (i.e., c-CHC) and intermediate cell type (i.e., i-CHC). c-CHC harbors both HCC and iCCA cells, whereas i-CHC is comprised of intermediate cell types lacking classical regions of HCC or iCCA cells. Notwithstanding the unique pathological feature of i-CHC, its molecular characteristics is not fully elucidated yet. Methods: To obtain molecular insights on the i-CHC, RNA-sequencing (RNA-Seq) and whole genome sequencing (WGS) profiling were performed on the tissues of i-CHC, HCC, and iCCA, respectively. Results: i-CHC showed unique transcriptomic features differing from HCC and iCCA, showing higher expression of Notch signaling and frequent splicing events of intron-retention (IR). Noticeably, we found that i-CHC had DNA-copy number loss and concomitant transcriptional suppression of METTL16, which may contribute to the aggressive progression of i-CHC via Notch activation. Conclusions: We suggest that i-CHC had unique transcriptomic features, providing new insights into the pathobiology of i-CHC.

2024-08-14 | GSE241466 | GEO

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