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Concurrent Disruption of Ras-Erk and NF-κB Pathways Induces Circadian Deregulation and Hepatocarcinogenesis

ABSTRACT: Mice with hepatocyte-specific deletion of both Shp2 and IkkB were generated, which disrupted basal levels of Ras-ERK and NF-kB signaling. These mice exhibited accelerated liver tumor formation compared to either single knockout alone. RNA-Seq analysis of whole liver and isolated hepatocytes from all genotypes were performed to identify tumor-promoting factors in the DKO model. Along with inflammatory and

ORGANISM(S): Mus musculus

PROVIDER: GSE158381 | GEO | 2021/12/01

REPOSITORIES: GEO

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Concurrent Disruption of the Ras/MAPK and NF-κB Pathways Induces Circadian Deregulation and Hepatocarcinogenesis.

Project description:The Ras/Erk and NF-κB pathways play critical roles in cell proliferation and are known to drive oncogenesis when overactivated. Herein we report a gatekeeper function of the two pathways by working in synergy to suppress liver tumorigenesis. Hepatocyte-specific deletion of both Shp2/Ptpn11 and Ikkβ in mice, which promote Ras/Erk and NF-κB signaling, respectively, exacerbated chemical carcinogenesis and even triggered spontaneous development of hepatocellular carcinoma (HCC). We show that the unanticipated severe tumor phenotype was contributed collectively by severe cholestasis, metabolic changes, upregulated cell-cycle progression, and disruption of circadian rhythm in mutant hepatocytes. Remarkably, human HCCs with dysregulated circadian gene expression displayed downregulation of Ras/Erk and NF-κB signaling and poor prognosis. Together, these data indicate that at the ground state, the two central pathways, previously known as oncogenic, cooperate to sustain tumor-suppressive physiologic homeostasis and to prevent hepatic damage. Disruption of this intricate signaling network is carcinogenic in the liver.ImplicationsWe demonstrate here that basal levels of the Ras/MAPK and NF-κB pathways, while promoting tumorigenesis if overactivated, are required to maintain physiologic homeostasis and regulate circadian rhythm in the liver, which are antitumorigenic.

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Concurrent Disruption of Ras-Erk and NF-κB Pathways Induces Circadian Deregulation and Hepatocarcinogenesis

Project description:Concurrent Disruption of Ras-Erk and NF-κB Pathways Induces Circadian Deregulation and Hepatocarcinogenesis

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Deregulation of the Ras-Erk Signaling Axis Modulates the Enhancer Landscape.

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Project description:Microarray analysis of WT (Pten2fl/fl:Shp2fl/fl:Alb-Cre-), SKO (Shp2hep-/-, or Shp2fl/fl:Alb-Cre+), PKO (Ptenhep-/-, or Pten2fl/fl:Alb-Cre+) and DKO (Ptenfl/fl:Shp2fl/fl:Alb-Cre+) liver samples to gain global molecular insights how shp2 and pten is involved in liver tumorigenesis.

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Temporal gene expression patterns (Next Generation Sequencing) in liver tumourigenesis of hepatocyte-specific deletion of shp2 and/or pten

Project description:Purpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goals of this study are to reveal dynamics of liver tumourigenesis in different mouse model and identify some key regulators that control HCC initiation or progression. We also try to define a index based on transcriptome of samples to quantify tumor development stage. Methods: mRNA profiles of wild-type (WT), hepatocyte-specific shp2 deletion (Shp2−/−) mice (SKO), hepatocyte-specific pten deletion (Pten−/−) mice (PKO), and hepatocyte-specific shp2 and pten deletion mice (DKO) were generated by deep sequencing. The sequence reads that passed quality filters were mapped to Mouse genome using STAR, and mRNA profiles were obtained using cuffdiff. Results: quanlity control of mRNA profiles showed that the data captured key features of phenotypes. Significantly changed genes, pathways, biolgocial processes, ligand and receptor, epigenetic regulators et al of SKO, PKO, DKO mice at differnet age were obtaiend. Temporal gene expression patterns during liver tumorigenesis in SKO, PKO and DKO mice were obtained. Conclusions: Our study represents the first detailed analysis of temporal transcriptomes during liver tumourigenesis, with biologic replicates, generated by RNA-seq technology. The optimized data analysis workflows reported here should provide a framework for comprehensive investigations of expression profiles.

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Deregulation of the Ras-Erk Signaling Axis Modulates the Enhancer Landscape

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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Deregulation of the Ras-Erk Signaling Axis Modulates the Enhancer Landscape

Project description:This SuperSeries is composed of the SubSeries listed below.

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Deregulation of the Ras-Erk Signaling Axis Modulates the Enhancer Landscape [RNA-seq]

Project description:Unrestrained receptor tyrosine kinase (RTK) signaling and epigenetic deregulation are root causes of tumorigenesis. We establish linkage between these processes by demonstrating that aberrant RTK signaling unleashed by oncogenic HRasG12V or loss of negative feedback through Sprouty gene deletion remodels histone modifications associated with active typical and super-enhancers. However, while both lesions disrupt the Ras-Erk axis, the expression programs, enhancer signatures, and transcription factor networks modulated upon HRasG12V-transformation or Sprouty deletion are largely distinct. Oncogenic HRasG12V elevates histone 3 lysine 27 acetylation (H3K27ac) levels at enhancers near the transcription factor Gata4 and the kinase Prkcb, as well as their expression levels. We show that Gata4 is necessary for the aberrant gene expression and H3K27ac marking at enhancers, and Prkcb is required for the oncogenic effects of HRasG12V-driven cells. Taken together, our findings demonstrate that dynamic reprogramming of the cellular enhancer landscape is a major effect of oncogenic RTK signaling. We assessed gene expression changes upon loss of feedback regulation through Sprouty (Spry) deletion, and upon unrestrained signaling driven by mutant oncogenes. RNA-seq was performed in biological triplicate; replicate number is included in the sample name. Spry124fl/fl (VEC) and Spry124-/- (CRE) MEFs were profiled in three conditions: unsynchronized (U), serum starved (S), and serum starved and FGF treated (F). Spry124fl/fl (VEC) MEFs transduced with empty vector (EV) control or the indicated oncogenes (KRasG12V, HRasG12V, and BRafV600E) as well as Spry124-/- (CRE) MEFs transduced with EV control were profiled in the unsynchronized state.

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Deregulation of the Ras-Erk Signaling Axis Modulates the Enhancer Landscape [ChIP-seq]

Project description:Unrestrained receptor tyrosine kinase (RTK) signaling and epigenetic deregulation are root causes of tumorigenesis. We establish linkage between these processes by demonstrating that aberrant RTK signaling unleashed by oncogenic HRasG12V or loss of negative feedback through Sprouty gene deletion remodels histone modifications associated with active typical and super-enhancers. However, while both lesions disrupt the Ras-Erk axis, the expression programs, enhancer signatures, and transcription factor networks modulated upon HRasG12V-transformation or Sprouty deletion are largely distinct. Oncogenic HRasG12V elevates histone 3 lysine 27 acetylation (H3K27ac) levels at enhancers near the transcription factor Gata4 and the kinase Prkcb, as well as their expression levels. We show that Gata4 is necessary for the aberrant gene expression and H3K27ac marking at enhancers, and Prkcb is required for the oncogenic effects of HRasG12V-driven cells. Taken together, our findings demonstrate that dynamic reprogramming of the cellular enhancer landscape is a major effect of oncogenic RTK signaling. We performed ChIP-seq to assess the global changes in the histone modifications H3K27ac (AC), H3K4me1 (me1), and H3K4me3 (me3) upon loss of feedback regulation through Sprouty (Spry) deletion, and upon unrestrained signaling driven by oncogenic HRasG12V. ChIP-seq was performed in biological duplicate; replicate2 is indicated in the sample name. Spry124fl/fl (VEC) and Spry124-/- (CRE) MEFs were profiled in three conditions: unsynchronized (U), serum starved (S), and serum starved and FGF treated (F). Spry124fl/fl (VEC) MEFs transduced with empty vector (EV) control or HRasG12V (HRas) were profiled in the unsynchronized state.

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