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GSE61100
Mus musculus
9 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Overexpression of p21 in NEMOhepa animals protects against DNA damage, acceleration of hepatocarcinogenesis and cholestasis. As strengthened by our LPS stimulation experiments, we identified a novel protective role of p21 against DNA damage.
Publication Title
p21 ablation in liver enhances DNA damage, cholestasis, and carcinogenesis.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 24 Downloadable Samples
- Affymetrix Mouse Gene 1.1 ST Array (mogene11st)
Description
Hepatic fibrosis is a wound-healing response to chronic liver injury, which may result in cirrhosis and liver failure. The c-Jun N-terminal kinase-1 (JNK1) gene has been shown to be involved in liver fibrosis. Here, we aimed to investigate the molecular mechanism and identify the cell-type involved in mediating the JNK1-dependent effect on liver fibrogenesis Wild-type (WT), JNK1/ and JNK1hepa (hepatocyte-specific deletion of JNK1) mice were subjected to bile duct ligation (BDL). Additionally, we performed bone marrow transplantations (BMT), isolated primary hepatic stellate cells (HSCs) and studied their activation in vitro. Serum markers of liver damage (liver transaminases, alkaline phosphatase and bilirubin) and liver histology revealed reduced injury in JNK1/ compared to WT and JNK1hepa mice. Hepatocyte cell death and proliferation was reduced in JNK1/ compared to WT and JNK1hepa. Parameters of liver fibrosis such as Sirius Red staining as well as Collagen IA1 and SMA expression were down-regulated in JNK1/ compared to WT and JNK1hepa livers, 4 weeks after BDL. To delineate the essential cell-type, we performed BMT of WT and JNK1-/- into JNK1-/- and WT mice, respectively. BMT experiments excluded bone marrow derived cells from having a major impact on the JNK1-dependent effect on fibrogenesis. Hence, we investigated primary HSCs from JNK1/ livers showing reduced transdifferentiation compared with WT and JNK1hepa-derived HSCs. We conclude that JNK1 in HSCs plays a crucial role in hepatic fibrogenesis and thus represents a promising target for cell-directed treatment options for liver fibrosis.
Publication Title
Jnk1 in murine hepatic stellate cells is a crucial mediator of liver fibrogenesis.
Sample Metadata Fields
Sex, Age, Specimen part, Treatment, Time
View Samples- Mus musculus
- 11 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Death receptor-mediated hepatocyte apoptosis is implicated in a wide range of liver diseases including viral hepatitis, alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic liver injury and cancer. Deletion of NF-B essential modulator in hepatocytes (Nemohepa) causes the spontaneous development of hepatocellular carcinoma preceded by steatohepatitis in mice and thus serves as an excellent model for the progression from chronic hepatitis to liver cancer. In the present study we aimed to dissect the death-receptor mediated pathways that contribute to liver injury in Nemohepa mice. Therefore, we generated Nemohepa/TRAIL-/- and Nemohepa/TNFR1-/- animals and analyzed the progression of liver injury. Nemohepa/TRAIL-/- displayed a similar phenotype to Nemohepa mice characteristic of high apoptosis, infiltration of immune cells, hepatocyte proliferation and steatohepatitis. These pathophysiological features were significantly ameliorated in Nemohepa/TNFR1-/- livers. Hepatocyte apoptosis was increased in Nemohepa and Nemohepa/TRAIL-/- mice while Nemohepa/TNFR1-/- animals showed reduced cell death concomitant with a strong reduction in pJNK levels. Cell cycle parameters were significantly less activated in Nemohepa/TNFR1-/- livers. Additionally, markers of liver fibrosis and indicators of tumour progression were significantly decreased in these animals. The present data demonstrate that the death receptor TNFR1 but not TRAIL is important in determining progression of liver injury in hepatocyte-specific Nemo knockout mice.
Publication Title
TNFR1 determines progression of chronic liver injury in the IKKγ/Nemo genetic model.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 24 Downloadable Samples
- Affymetrix Mouse Gene 1.1 ST Array (mogene11st)
Description
Aberrant biliary hyperproliferation resulting from lack of differentiating signals favoring the maintenance of an immature and proliferative phenotype by biliary epithelial cells are ultimately responsible for ducto/cystogenesis and intrahepatic cholangiocarcinoma (CCA) formation. Mitogen-activated protein kinase (MAPK) signaling is pivotal for CCA-related tumorigenesis. In particular, targeted inhibition of JNK signaling has shown therapeutic potential. However, the cell-type specific role and mechanisms triggered by JNK in liver parenchymal cells during CCA remains largely unknown. Here, we aimed to investigate the relevance of JNK function in hepatocytes in experimental carcinogenesis. JNK signaling in hepatocytes was inhibited by crossing AlbCre-JNK1LoxP/LoxP mice with JNK2-deficient mice to generate Jnk1LoxP/LoxP/Jnk2−/− (JNKΔhepa) mice. JNKΔhepa mice were further interbred with hepatocyte-specific Nemo-knockout mice (NEMOΔhepa), a model of chronic liver inflammation and spontaneous hepatocarcinogenesis, to generate NEMO/JNKΔhepa mice. The impact of JNK deletion on liver damage, cell death, compensatory proliferation, fibrogenesis, and tumor development in NEMOΔhepa mice was determined. Moreover, regulation of essential genes was assessed by RT-PCR, immunoblottings and immunostains. Additionally, JNK2 inhibition, specifically in hepatocytes of NEMOΔhepa/JNK1Δhepa mice, was performed using siRNA (siJnk2) nanodelivery. Finally, active signaling pathways were blocked using specific inhibitors. Compound deletion of JNK1 and JNK2 in hepatocytes diminished hepatocarcinogenesis in both the DEN model of hepatocarcinogenesis and in NEMOΔhepa mice, but, in contrast, caused massive proliferation of the biliary ducts. Indeed, JNK deficiency in hepatocytes of NEMOΔhepa (NEMOΔhepa/JNKΔhepa) animals caused elevated fibrosis, increased apoptosis, increased compensatory proliferation, and elevated inflammatory cytokines expression, but reduced hepatocarcinogenesis. Furthermore, siJnk2 treatment in NEMOΔhepa/JNK1Δhepa mice recapitulated the phenotype of NEMOΔhepa/JNKΔhepa mice. Next, we sought to investigate the impact of molecular pathways in response to compound JNK deficiency in NEMOΔhepa mice. We found that NEMOΔhepa/JNKΔhepa livers exhibited overexpression of the IL-6/Stat3 pathway in addition to EGFR-Raf-MEK-ERK cascade. The functional relevance was tested by administering lapatinib - a dual tyrosine kinase inhibitor (TKI) of ErbB2 and EGFR signaling - to NEMOΔhepa/JNKΔhepa mice. Lapatinib effectively inhibited cystogenesis, improved transaminases and effectively blocked EGFR-Raf-MEK-ERK signaling. Our study defines a novel function of JNK in cell fate as well as hepatocarcinogenesis and opens new therapeutic avenues devised to inhibit pathways of cholangiocarcinogenesis.
Publication Title
Loss of c-Jun N-terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma.
Sample Metadata Fields
Age, Specimen part, Treatment
View Samples- Mus musculus
- 17 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Tumor growth is associated with a profound alteration of myelopoiesis, leading to recruitment of immunosuppressive cells known as myeloid-derived suppressor cells (MDSCs). Immuno-regulatory activity of both tumor-induced and BM-derived MDSCs (by GM-CSF and IL-6 treatment) was entirely dependent on C/EBP transcription factor (TF), a key component of the emergency myelopoiesis triggered by stress and inflammation. We used miR expression analysis to identify miRs which could drive MDSC recruitment/generation/activity by modulating specific TFs and pathway. In particular, we identified a miR signature of 79 miR differentially expressed between not suppressive CD11b+ cells and CD11b+ isolated from tumor mass and spleen of tumor-bearing mice. Moreover on the same samples we profiled gene expression with Affymetrix microarrays to perform an integrated analysis of mirna and gene expression.
Publication Title
miR-142-3p prevents macrophage differentiation during cancer-induced myelopoiesis.
Sample Metadata Fields
Specimen part, Disease, Disease stage, Cell line
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Tumor progression is accompanied by an altered myelopoiesis that causes the accumulation of cells inhibiting anti-tumor T lymphocytes. We previously reported that immunosuppressive cells can be generated in vitro from bone marrow cells (BM) after four days GM-CSF and IL-6 treatment. Here, we describe that miR-142-3p down-regulation directs macrophage differentiation and determines the acquisition of their immunosuppressive function in cancer. Enforced miR over-expression impaired monocyte to macrophage transition both in vitro and in vivo. Conversely, forced miR down-regulation promoted the generation of immunosuppressive macrophages even during G-CSF-induced granulocytic differentiation. To identify how miR-142-3p regulates MDSC generation and activity, we analyze the gene expression of BM cultures transfected with either CTRL- or miR 142-3p mimic oligo -transfected before four days GM-CSF and IL-6 treatment.
Publication Title
miR-142-3p prevents macrophage differentiation during cancer-induced myelopoiesis.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 12 Downloadable Samples
- Affymetrix Mouse Gene 1.1 ST Array (mogene11st)
Description
BACKGROUND & AIMS:
Publication Title
Combined Activities of JNK1 and JNK2 in Hepatocytes Protect Against Toxic Liver Injury.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 15 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Chronic liver injury triggers complications such as liver fibrosis and hepatocellular carcinoma (HCC), which are associated with alterations in distinct signaling pathways. Of particular interest is the interaction between mechanisms controlled by IKK/NEMO, the regulatory IKK subunit, and Jnk activation for directing cell death and survival. In the present study, we aimed to define the relevance of Jnk in hepatocyte-specific NEMO knockout mice (NEMOhepa), a genetic model of chronic inflammatory liver injury. We generated global Jnk1-/-/NEMOhepa and Jnk2-/-/NEMOhepa mice by crossing NEMOhepa mice with Jnk1-/- and Jnk2-/- animals, respectively, and examined the progression of chronic liver disease. Moreover, we investigated the expression of Jnk during acute liver injury, evaluated the role of Jnk1 in bone marrow-derived cells, and analyzed the expression of NEMO and pJnk in human diseased-livers. Deletion of Jnk1 significantly aggravated the progression of liver disease, exacerbating apoptosis, compensatory proliferation and carcinogenesis in NEMOhepa mice. Jnk2-/-/NEMOhepa showed increased RIP-1 and RIP-3 expression and hepatic inflammation. Jnk1 in hematopoietic cells rather than hepatocytes had an impact on the progression of chronic liver disease in NEMOhepa livers. These findings are of clinical relevance since NEMO expression was down-regulated in hepatocytes of patients with HCC whereas NEMO and pJnk were expressed in a large amount of infiltrating cells. While Jnk1 is protective in NEMOhepa-depleted hepatocytes, Jnk1 in hematopoietic cells rather than hepatocytes is a crucial driver of hepatic injury. These results elucidate the complex function of Jnk in chronic inflammatory liver disease.
Publication Title
Haematopoietic cell-derived Jnk1 is crucial for chronic inflammation and carcinogenesis in an experimental model of liver injury.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 35 Downloadable Samples
- Affymetrix Mouse Gene 1.1 ST Array (mogene11st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
microRNA 193a-5p Regulates Levels of Nucleolar- and Spindle-Associated Protein 1 to Suppress Hepatocarcinogenesis.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 35 Downloadable Samples
- Affymetrix Mouse Gene 1.1 ST Array (mogene11st)
Description
BACKGROUND & AIMS: We performed an integrated analysis to identify microRNAs (miRNAs) and mRNAs with altered expression in liver tumors from 3 mouse models of hepatocellular carcinoma (HCC) and human tumor tissues.
Publication Title
microRNA 193a-5p Regulates Levels of Nucleolar- and Spindle-Associated Protein 1 to Suppress Hepatocarcinogenesis.
Sample Metadata Fields
Specimen part
View Samples