Diverse MicroRNAs-mRNA networks regulate the priming phase of mouse liver regeneration and of direct hyperplasia
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE185316 | GEO | 2022/01/21
REPOSITORIES: GEO
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Project 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 HNF4α 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. We used microarrays to detail the global programme of gene expression in [METKO + EGFRi] mice liver following TCPOBOP treatment
2018-08-28 | GSE110695 | GEO
Project description:The liver is the only organ in mammals, which fully regenerates after injury. To identify novel regulators of liver regeneration, we performed quantitative large-scale proteomics analysis of subcellular fractions from normal versus regenerating mouse liver. Proteins of the ubiquitin-proteasome pathway were rapidly regulated by partial hepatectomy, with the ubiquitin ligase Nedd4-1 being among the top hits. Knock-down of Nedd4-1 in hepatocytes in vivo through nanoparticle-mediated delivery of siRNA caused severe liver damage after partial hepatectomy and impaired regeneration, resulting in liver failure. Mechanistically, we demonstrate that Nedd4-1 is required for efficient activation of Erk1/2 signaling by receptor tyrosine kinases involved in liver regeneration through inhibition of receptor internalization, thus controlling a major pro-mitogenic and cytoprotective signaling pathway in the regenerating liver. These results highlight the power of large-scale proteomics to identify key players in liver regeneration and the importance of posttranslational regulation of growth factor signaling in this process.
2017-09-13 | PXD004108 | Pride
Project description:High doses of sodium phenobarbital (NaPB), a constitutive androstane receptor (CAR) activator, have been shown to produce hepatocellular tumors in rodents by a mitogenic mode of action (MOA) involving CAR activation. The effect of 1 week dietary treatment with NaPB on liver weight and histopathology, hepatic CYP2B enzyme activity and CYP2B/3A mRNA expression, replicative DNA synthesis and selected genes related to cell proliferation and functional transcriptomic and metabolomic analyses was studied in male CD-1 mice, Wistar Hannover (WH) rats and chimeric mice with human hepatocytes. The treatment of chimeric mice with 1000-1500 ppm NaPB resulted in plasma levels around 3-5 fold higher than those observed in human subjects given therapeutic doses of NaPB. NaPB produced dose-dependent increases in hepatic CYP2B activity and CYP2B/3A mRNA levels in all animal models. Integrated functional metabolomic and transcriptomic analyses demonstrated the responses to NaPB in human liver were clearly different from those in rodents. While NaPB produced a dose-dependent increase in hepatocyte replicative DNA synthesis in CD-1 mice and WH rats, no increase in replicative DNA synthesis was observed in human hepatocyte-originated areas of chimeric mice. In addition, treatment with NaPB had no effect on Ki-67, PCNA, GADD45β, and MDM2 mRNA expression in chimeric mice, whereas significant increases were observed in CD-1 mice and/or WH rats. Thus, while NaPB could activate CAR in rodent and human hepatocytes, NaPB did not increase replicative DNA synthesis in human hepatocytes of chimeric mice, whereas it was mitogenic to rat and mouse hepatocytes. As human hepatocytes are refractory to the mitogenic effects of NaPB, the MOA for NaPB-induced rodent liver tumor formation is thus not relevant for humans. Male CD-1 mice were fed diets containing 0 (control) or 2500 ppm NaPB for 7 days. Liver samples were used for gene expression analysis.
2014-08-29 | E-GEOD-57055 | biostudies-arrayexpress
Project description:High doses of sodium phenobarbital (NaPB), a constitutive androstane receptor (CAR) activator, have been shown to produce hepatocellular tumors in rodents by a mitogenic mode of action (MOA) involving CAR activation. The effect of 1 week dietary treatment with NaPB on liver weight and histopathology, hepatic CYP2B enzyme activity and CYP2B/3A mRNA expression, replicative DNA synthesis and selected genes related to cell proliferation and functional transcriptomic and metabolomic analyses was studied in male CD-1 mice, Wistar Hannover (WH) rats and chimeric mice with human hepatocytes. The treatment of chimeric mice with 1000-1500 ppm NaPB resulted in plasma levels around 3-5 fold higher than those observed in human subjects given therapeutic doses of NaPB. NaPB produced dose-dependent increases in hepatic CYP2B activity and CYP2B/3A mRNA levels in all animal models. Integrated functional metabolomic and transcriptomic analyses demonstrated the responses to NaPB in human liver were clearly different from those in rodents. While NaPB produced a dose-dependent increase in hepatocyte replicative DNA synthesis in CD-1 mice and WH rats, no increase in replicative DNA synthesis was observed in human hepatocyte-originated areas of chimeric mice. In addition, treatment with NaPB had no effect on Ki-67, PCNA, GADD45β, and MDM2 mRNA expression in chimeric mice, whereas significant increases were observed in CD-1 mice and/or WH rats. Thus, while NaPB could activate CAR in rodent and human hepatocytes, NaPB did not increase replicative DNA synthesis in human hepatocytes of chimeric mice, whereas it was mitogenic to rat and mouse hepatocytes. As human hepatocytes are refractory to the mitogenic effects of NaPB, the MOA for NaPB-induced rodent liver tumor formation is thus not relevant for humans. Male WH rats (4 animals/dose) were fed diets containing 0 (control) or 2500 ppm NaPB for 7 days. Liver samples were used for gene expression analysis.
2014-08-29 | E-GEOD-57057 | biostudies-arrayexpress
Project description:Using a chimeric mouse humanized liver model, we provided evidence that human hepatocytes are refractory to the mitogenic effects of rodent constitutive androstane receptor (CAR) activators. To evaluate the functional reliability of this model, the present study examined mitogenic responses to phenobarbital (PB) in chimeric mice transplanted with rat hepatocytes, since rats are responsive to CAR activators. Treatment with 1000 ppm PB for 7 days significantly increased replicative DNA synthesis (RDS) in rat hepatocytes of the chimeric mice, demonstrating that the transplanted hepatocyte model is functionally reliable for cell proliferation analysis. Treatment of humanized CAR and pregnane X receptor (PXR) mice (hCAR/hPXR mice) with 1000 ppm PB for 7 days significantly increased hepatocyte RDS together with increases in several mitogenic genes. Global gene expression analysis was performed with liver samples from this and from previous studies focusing on PB-induced Wnt/β-catenin signaling, and showed that altered genes in hCAR/hPXR mice clustered most closely with liver tumor samples from a diethylnitrosamine/PB initiation/promotion study than with wild type mice. However, different gene clusters were observed for chimeric mice with human hepatocytes for Wnt/ß-catenin signaling when compared to those of hCAR/hPXR mice, wild type mice and liver tumor samples. The results of this study demonstrate clear differences in the effects of PB on hepatocyte RDS and global gene expression between human hepatocytes of chimeric mice and hCAR/hPXR mice, suggesting that the chimeric mouse model is relevant to humans for studies on the hepatic effects of rodent CAR activators, whereas the hCAR/hPXR mouse is not.
2021-04-20 | GSE149230 | GEO
Project description:Using a chimeric mouse humanized liver model, we provided evidence that human hepatocytes are refractory to the mitogenic effects of rodent constitutive androstane receptor (CAR) activators. To evaluate the functional reliability of this model, the present study examined mitogenic responses to phenobarbital (PB) in chimeric mice transplanted with rat hepatocytes, since rats are responsive to CAR activators. Treatment with 1000 ppm PB for 7 days significantly increased replicative DNA synthesis (RDS) in rat hepatocytes of the chimeric mice, demonstrating that the transplanted hepatocyte model is functionally reliable for cell proliferation analysis. Treatment of humanized CAR and pregnane X receptor (PXR) mice (hCAR/hPXR mice) with 1000 ppm PB for 7 days significantly increased hepatocyte RDS together with increases in several mitogenic genes. Global gene expression analysis was performed with liver samples from this and from previous studies focusing on PB-induced Wnt/β-catenin signaling, and showed that altered genes in hCAR/hPXR mice clustered most closely with liver tumor samples from a diethylnitrosamine/PB initiation/promotion study than with wild type mice. However, different gene clusters were observed for chimeric mice with human hepatocytes for Wnt/ß-catenin signaling when compared to those of hCAR/hPXR mice, wild type mice and liver tumor samples. The results of this study demonstrate clear differences in the effects of PB on hepatocyte RDS and global gene expression between human hepatocytes of chimeric mice and hCAR/hPXR mice, suggesting that the chimeric mouse model is relevant to humans for studies on the hepatic effects of rodent CAR activators, whereas the hCAR/hPXR mouse is not.
2021-04-20 | GSE149229 | GEO
Project description:Using a chimeric mouse humanized liver model, we provided evidence that human hepatocytes are refractory to the mitogenic effects of rodent constitutive androstane receptor (CAR) activators. To evaluate the functional reliability of this model, the present study examined mitogenic responses to phenobarbital (PB) in chimeric mice transplanted with rat hepatocytes, since rats are responsive to CAR activators. Treatment with 1000 ppm PB for 7 days significantly increased replicative DNA synthesis (RDS) in rat hepatocytes of the chimeric mice, demonstrating that the transplanted hepatocyte model is functionally reliable for cell proliferation analysis. Treatment of humanized CAR and pregnane X receptor (PXR) mice (hCAR/hPXR mice) with 1000 ppm PB for 7 days significantly increased hepatocyte RDS together with increases in several mitogenic genes. Global gene expression analysis was performed with liver samples from this and from previous studies focusing on PB-induced Wnt/β-catenin signaling, and showed that altered genes in hCAR/hPXR mice clustered most closely with liver tumor samples from a diethylnitrosamine/PB initiation/promotion study than with wild type mice. However, different gene clusters were observed for chimeric mice with human hepatocytes for Wnt/ß-catenin signaling when compared to those of hCAR/hPXR mice, wild type mice and liver tumor samples. The results of this study demonstrate clear differences in the effects of PB on hepatocyte RDS and global gene expression between human hepatocytes of chimeric mice and hCAR/hPXR mice, suggesting that the chimeric mouse model is relevant to humans for studies on the hepatic effects of rodent CAR activators, whereas the hCAR/hPXR mouse is not.
2021-04-20 | GSE149228 | GEO
Project description:Activation of Wnt/β-catenin signaling is frequent in human and rodent hepatocarcinogenesis. Although in mice, the tumor promoting activity of agonists of constitutive androstane receptor (CAR) occurs via selection of carcinogen-initiated cells harbouring β-catenin mutations, the molecular alterations leading to hepatocellular carcinoma (HCC) development by The CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), in the absence of genotoxic injury are unknown. Here we show that CAR activation per se induced HCC in mice and that 91% of them carried β-catenin point mutations or large in-frame deletions/exon skipping targeting Ctnnb1 exon 3. Point mutations in HCCs induced by TCPOBOP alone displayed different nucleotide substitutions compared to those found in HCCs from mice pre-treated with diethylnitrosamine (DENA). Moreover, unlike those occurring in HCCs from DENA+TCPOBOP mice, they did not result in increased expression of β-catenin target genes, such as Glul, Lgr5, Rgn, Lect2 and Ccnd1, or nuclear translocation of β-catenin when compared to the control liver. Remarkably, in the non-tumoral liver tissue, chronic CAR activation led to down-regulation of these genes and to a partial loss of glutamine synthetase (GS)-positive hepatocytes. These results thus show that while chronic CAR activation per se induces HCCs carrying β-catenin mutations, it concurrently down-regulates the Wnt/β-catenin pathway in non-tumoral liver. They also indicate that the relationship between CAR and β-catenin may be profoundly different between normal and neoplastic hepatocytes.
2018-04-27 | GSE113708 | GEO
Project description:Changes in the activating histone-H3 chromatin marks K4me1, K4me3, and K27ac were assayed in male mouse liver following exposure to TCPOBOP, an agonist ligand of the nuclear receptor CAR (constitutive androstane receptor). This work is part of a larger study, entitled: "Widespread Epigenetic Changes to the Enhancer Landscape of Mouse Liver Induced by a Specific Xenobiotic Agonist Ligand of the Nuclear Receptor CAR" (Tox Sci, 2019).
2020-04-28 | GSE104060 | GEO
Project description:The recovery of liver mass is mainly mediated by proliferation and enlargement of hepatocytes after partial hepatectomy. Studying the gene expression profiles of hepatocytes after partial hepatectomy will be helpful in exploring the mechanism of liver regeneration. We used microarrays to further highlight the regulatory role of hepatocyte in liver regeneration at gene transcription level.
2014-02-28 | GSE55434 | GEO