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GSE110695
Mus musculus
8 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
TCPOBOP (1,4-Bis [2-(3,5-Dichloropyridyloxy)] benzene) is a constitutive androstane receptor (CAR) agonist that induces robust hepatocyte proliferation and hepatomegaly without any liver injury or tissue loss. TCPOBOP-induced direct hyperplasia has been considered to be CAR-dependent with no evidence of involvement of cytokines or growth factor signaling. Receptor tyrosine kinases (RTKs), MET and EGFR, are known to play a critical role in liver regeneration after partial hepatectomy, but their role in TCPOBOP-induced direct hyperplasia, not yet explored, is investigated in the current study. Disruption of the RTK-mediated signaling was achieved utilizing MET KO mice along with Canertinib treatment for EGFR inhibition. Combined elimination of MET and EGFR signaling [MET KO + EGFRi], but not individual disruption, dramatically reduced TCPOBOP-induced hepatomegaly and hepatocyte proliferation. TCPOBOP-driven CAR activation was not altered in [MET KO + EGFRi] mice, as measured by nuclear CAR translocation and analysis of typical CAR target genes. However, TCPOBOP induced cell cycle activation was impaired in [MET KO + EGFRi] mice due to defective induction of cyclins, which regulate cell cycle initiation and progression. TCPOBOP-driven induction of FOXM1, a key transcriptional regulator of cell cycle progression during TCPOBOP-mediated hepatocyte proliferation, was greatly attenuated in [MET KO + EGFRi] mice. Interestingly, TCPOBOP treatment caused transient decline in HNF4 expression concomitant to proliferative response; this was not seen in [MET KO + EGFRi] mice. Transcriptomic profiling revealed vast majority (~40%) of TCPOBOP-dependent genes mainly related to proliferative response, but not to drug metabolism, were differentially expressed in [MET KO + EGFRi] mice. Conclusion: Taken together, combined disruption of EGFR and MET signaling lead to dramatic impairment of TCPOBOP-induced proliferative response without altering CAR activation.
Publication Title
TCPOBOP-induced hepatomegaly & hepatocyte proliferation is attenuated by combined disruption of MET & EGFR signaling.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
MET and EGFR receptor tyrosine kinases are crucial for liver regeneration and normal hepatocyte function. Recently we demonstrated that in mice, combined inhibition of these two signaling pathways abolished liver regeneration following hepatectomy, with subsequent hepatic failure and death at 15-18 days post-resection. Morbidity was associated with distinct and specific alterations in important downstream signaling pathways that led to a decrease in hepatocyte volume, reduced proliferation, and shutdown of many essential hepatocyte functions such as fatty acid synthesis, urea cycle, and mitochondrial functions. In the present study we explore the role of MET and EGFR signaling in resting mouse livers that are not subjected to hepatectomy. Mice with combined disruption of MET and EGFR signaling (Delta MET + EGFRi) were noticeably sick by 10 day and died at 12-14 days. Delta MET + EGFRi mice showed decreased liver to body weight ratios, increased apoptosis in non-parenchymal cells, impaired liver metabolic functions, and activation of distinct, downstream signaling pathways related to inflammation, cell death, and survival. Conclusion: The present study demonstrates that in addition to controlling the regenerative response, MET and EGFR synergistically control baseline liver homeostasis in normal mice in such a way that their combined disruption leads to liver failure and death.
Publication Title
Combined Systemic Disruption of MET and Epidermal Growth Factor Receptor Signaling Causes Liver Failure in Normal Mice.
Sample Metadata Fields
Time
View Samples- Mus musculus
- 2 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
It has been shown that up regulation activity of CD81(TAPA-1, the portal of entry of Hepatitis C virus) by agonistic antibody results in phosphorylation of Ezrin. We have previously shown that in liver, Ezrin phosphorylation occurs via Syk kinase, causing suppression of hippo intensity, therefore increases sequential Yap activity. The opposite occurs when Glypican-3 (GPC3) or E2 protein of HCV bind to CD81. Mice over-expressing GPC3 in hepatocytes have decreased p-Ezrin(Thr567) and Yap, increased Hippo activity and suppressed liver regeneration. The role of Ezrin in these processes has been speculated, but not proven. We now provide dynamic picture of Ezrin regulates Hippo pathway and Yap. Forced expression of plasmids expressing mutant Ezrin (T567D) (which mimics p-Ezrin(Thr567)) suppressed Hippo activity and activated Yap signaling. And this mutant Ezrin drive more cell proliferation to cell division through up regulated Yap activity in vitro and in vivo. CD81 loses expression, while p-Ezrin(Thr567) increases in JM1 and JM2 hepatocellular carcinoma (HCC) cells. Administration with compound NSC668394, a characterized p-Ezrin(Thr567) antagonist, caused significant decrease in HCC cell proliferation. We additionally present evidence that pEzrin(T567) is also controlled by EGFR and MET. Conclusions: Ezrin phosphorylation, mediated by CD81 associated Syk kinase, is directly involved in regulation of Hippo pathway, Yap levels and growth rates of normal and neoplastic hepatocytes. The finding has mechanistic and potentially therapeutic applications in understanding and regulating growth of hepatocytes and HCC and HCV pathogenesis.
Publication Title
Phosphorylated Ezrin (Thr567) Regulates Hippo Pathway and Yes-Associated Protein (Yap) in Liver.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Mice were fed with either normal diet (ND), 0.2% cholic acid diet (0.2%CA), DEN treated and fed ND or DEN treated and fed 0.2%CA diet. DEN was treated at 15 microgram/kg body weight at postnatal day 15. Diets were fed for two months starting 8 months of age till 10 months of age. Livers were collected at10 months of age, Total RNA was isolated and used for microarray experiments.
Publication Title
Bile acids promote diethylnitrosamine-induced hepatocellular carcinoma via increased inflammatory signaling.
Sample Metadata Fields
Age, Specimen part
View Samples- Mus musculus
- 24 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The cell of origin of hepatoblastoma in humans and mice (HB) is unknown; it has been hypothesized to be a transformed hepatocyte, an oval cell, or a multipotent hepatic progenitor cell. In mice, the current dogma is that HBs arise within hepatocellular neoplasms as a result of further transformation from a neoplastic hepatocyte. However, there is little evidence in the literature to support a direct relationship between these two cell types. Furthermore, due to differences in etiology and development of hepatoblastoma between mice and humans, many have questioned the relevance of these tumors in hazard identification and risk assessment. In order to better understand the relationship between hepatocellular carcinoma and hepatoblastoma, as well as better determine the molecular similarities between mouse and human hepatoblastoma, global gene expression analysis and targeted Hras and Ctnnb1 mutation analysis were performed using concurrent hepatoblastoma, hepatocellular carcinoma, and associated normal adjacent liver (in the context of vehicle control liver) samples from a recent National Toxicology Program chronic bioassay. The data from this study provides a better understanding of the origins of hepatoblastoma in the B6C3F1 mice and the relevance of mouse hepatoblastoma to humans when considering chemical exposures of potential human cancer risk.
Publication Title
Genomic Profiling Reveals Unique Molecular Alterations in Hepatoblastomas and Adjacent Hepatocellular Carcinomas in B6C3F1 Mice.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 7 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Genome-wide mapping of DNA hydroxymethylation in osteoarthritic chondrocytes.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 9 Downloadable Samples
Illumina HiSeq 2000, Illumina Genome Analyzer II
Description
Removal of introns by pre-mRNA splicing is a critical and in some cases rate-limiting step in mammalian gene expression. Deep sequencing of mouse embryonic stem cell RNA revealed many specific internal introns that are significantly more abundant than the other introns within poly(A) selected transcripts; we classify these as “detained” introns (DIs). We identified thousands of DIs flanking both constitutive and alternatively spliced exons in human and mouse cell lines. Drug inhibition of Clk SR-protein kinase activity triggered rapid splicing changes in a specific set of DIs, about half of which showed increased splicing and half increased intron detention, altering the transcript pool of over 300 genes. These data suggest a widespread mechanism by which a nuclear detained pool of mostly processed pre-mRNAs can be rapidly mobilized in response to stress or homeostatic autoregulation. Overall design: v6.5 mouse embryonic stem cells were untreated, treated with the Clk kinase inhibitor KH-CB19, or treated with DMSO as a negative control. Untreated cells were harvested and a single replicate was sequenced using a custom, ligation-based, stranded library preparation protocol. Treated cells were harvested at time 0 and at 2 hours post-treatment, and poly(A)-selected RNA-seq libraries were made from biological duplicates for each treatment/time, barcoded, and sequenced by strand-specific, paired-end sequencing using the Illumina TruSeq kit.
Publication Title
Detained introns are a novel, widespread class of post-transcriptionally spliced introns.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 7 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Examination of the genome-wide distribution of 5hmC in osteoarthritic chondrocytes compared to normal chondrocytes in order to elucidate the effect on OA-specific gene expression.
Publication Title
Genome-wide mapping of DNA hydroxymethylation in osteoarthritic chondrocytes.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 6 Downloadable Samples
- IlluminaHiSeq2000
Description
The epigenetic regulator BMI1 is upregulated in many human malignancies and has been implicated in cell migration, but the impact on autochthonous tumor progression is unexplored. Our analyses of human expression data show that BMI1 levels increase with progression in melanoma. We find that BMI1 expression in melanoma cells does not influence cell proliferation or primary tumor growth. In contrast, BMI1 levels are a key determinant of melanoma metastasis, whereby deletion impairs and overexpression enhances dissemination. Remarkably, BMI1’s pro-metastatic effect reflects enhancement of all stages of the metastatic cascade including invasion, migration, extravasation, adhesion and survival. Additionally, downregulation or upregulation of BMI1 induces sensitivity or resistance to BRAF inhibitor. Consistent with these pleiotropic effects, we find that BMI1 promotes widespread gene expression changes that encompass key hallmarks of the melanoma invasive signature, including activation of TGFß, non-canonical Wnt, EMT and EGF/PDGF pathways. Importantly, for both primary and metastatic melanoma samples, this BMI1-induced signature identifies invasive subclasses of human melanoma and predicts poor patient outcome. Our data yield key insights into melanoma biology and establish BMI1 as a compelling drug target whose inhibition would suppress both metastasis and chemoresistance. Overall design: Three replicates of A375 BMI1 or GFP overexpressing cells.
Publication Title
BMI1 induces an invasive signature in melanoma that promotes metastasis and chemoresistance.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Stable 5-Hydroxymethylcytosine (5hmC) Acquisition Marks Gene Activation During Chondrogenic Differentiation.
Sample Metadata Fields
Specimen part
View Samples