Influence of DEN in mice liver
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE57798 | GEO | 2014/06/06
SECONDARY ACCESSION(S): PRJNA248119
REPOSITORIES: GEO
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Project description:Hepatocellular carcinoma is the third leading cause of cancer death worldwide, and it is necessary to elucidate the mechanism of hepatocarcinogenesis. Hepatocellular carcinoma (HCC) has a high mortality rate and develops based on the chronic inflammatory hepatic disease. Therefore, novel prophylactic or therapeutic strategies are required to improve outcome. In this study, influence of diethylnitrosamine (DEN) and retinoic acid (ATRA) on hepatocarcinogenesis was investigated in mouse. These results suggest that the control of NF-M-NM-:B signaling during the early stage of HCC development is important for the prevention of malignant transformation in hepatocytes. Genes induced by the following treatments in mice liver were investigated at 2 days or 7 days after treatment; DEN: diethylnitrosamine (treatment of DEN (drinking water 80 mg/L)) ATRA: retinoic acid (treatment of ATRA (drinking water 30 mg/L)) G0s2 siRNA : G0s2 knockdown mouse liver (treatment of G0s2 siRNA) Control siRNA: treatment of scramble siRNA (negative control)
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Project description:Hepatocellular carcinoma is the third leading cause of cancer death worldwide, and it is necessary to elucidate the mechanism of hepatocarcinogenesis. Circadian clock systems have been related in cell cycle and carcinogenesis. In this study, hepatocarcinogenesis induced by DEN administration in mice was inhibited by knockdown of G0s2 at early stage in carcinogenesis. In addition, the circadian expression of G0s2 in mouse liver was regulated by RARα controlled by clock genes and ATRA. Moreover, mice administered both ATRA and DEN were not induced hepatocellular carcinoma, and decreased the expression of G0s2 at second day after the initiation of administration. These findings suggest that the control of G0s2 expression is important in carcinogenesis and G0s2 might be the novel target for prevention, diagnosis and treatment of hepatocellular carcinoma.
2013-08-01 | GSE39288 | GEO
Project description:Gene-expression profiles of rat hepatocellular carcinoma induced by diethylnitrosamine (DEN) and the effect of erlotinib Hepatocellular carcinoma (HCC) is the sixth most common solid tumor worldwide and the third leading cause of cancer-related death. Given the lack of successful treatment options, chemoprevention in high-risk patients has been proposed as an alternative strategy. Mounting evidence supports a role for epidermal growth factor (EGF) during chronic liver disease and hepatocellular transformation. We address the hypothesis that blocking the EGF-EGF receptor (EGFR) pathway may be an effective strategy for inhibiting fibrogenesis and hepatocarcinogenesis. A rat model of diethylnitrosamine (DEN)-induced cirrhosis was used to examine the effects of erlotinib on underlying chronic liver disease and HCC formation. The DEN-induced rat model closely resembles disease progression in humans both pathologically and molecularly. Erlotinib significantly prevented the development of HCC tumor nodules in a dose-dependent fashion. Further, erlotinib inhibited the activation of hepatic stellate cells and prevented fibrogenesis. Erlotinib also reduced hepatotoxicity and improved liver function. Finally, a gene expression signature predictive of poor survival in human cirrhosis patients was reversed in response to erlotinib. Our data demonstrate for the first time that EGFR inhibition prevents liver fibrogenesis. Further, our results suggest that erlotinib is a potentially effective HCC chemoprevention strategy through inhibition of cirrhosis progression which can be monitored at the molecular level.
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Project description:To better characterize the pathogenesis of hepatocarcinogenesis, we established mouse HCC model by diethylnitrosamine (DEN) exposures and performed whole genome expression profiling.
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Project description:Hepatocellular carcinoma (HCC) initiation is characterized by the sequential stepwise accumulation of molecular alterations. However, the earliest events during the dynamic temporal trend of hepatocarcinogenesis are still unknown. Using a diethylnitrosamine (DEN)-induced rat HCC model, we report a comprehensive transcriptomic landscape of liver tissues at the stages of hepatitis, cirrhosis, and HCC.
2020-11-10 | GSE141090 | GEO
Project description:Hepatocellular carcinoma is the third leading cause of cancer death worldwide, and it is necessary to elucidate the mechanism of hepatocarcinogenesis. Circadian clock systems have been related in cell cycle and carcinogenesis. In this study, hepatocarcinogenesis induced by DEN administration in mice was inhibited by knockdown of G0s2 at early stage in carcinogenesis. In addition, the circadian expression of G0s2 in mouse liver was regulated by RARM-NM-1 controlled by clock genes and ATRA. Moreover, mice administered both ATRA and DEN were not induced hepatocellular carcinoma, and decreased the expression of G0s2 at second day after the initiation of administration. These findings suggest that the control of G0s2 expression is important in carcinogenesis and G0s2 might be the novel target for prevention, diagnosis and treatment of hepatocellular carcinoma. Differential gene expression between G0s2 siRNA or Control siRNA transfected primary hepatocyte was measured after 24 hr of transfection.
2013-08-01 | E-GEOD-39288 | biostudies-arrayexpress
Project description:Hepatocellular carcinoma (HCC) is one of the leading cause of cancer-related mortality worldwide. Liver cirrhosis is well-established risk factor of HCC development, although prevention of HCC in cirrhosis patients is challenging. By utilizing bioinformatic compound screening based on a clinical HCC-risk-predicitve gene signature, we identified captopril as a potential HCC chemoprevention agent. We tested the drug in rats with diethylnitrosamine (DEN)-induced cirrhosis and HCC, and confirmed its HCC-preventive effect.
2022-08-02 | GSE157919 | GEO
Project description:Gene-expression profiles of rat hepatocellular carcinoma induced by diethylnitrosamine (DEN) and the effect of erlotinib Hepatocellular carcinoma (HCC) is the sixth most common solid tumor worldwide and the third leading cause of cancer-related death. Given the lack of successful treatment options, chemoprevention in high-risk patients has been proposed as an alternative strategy. Mounting evidence supports a role for epidermal growth factor (EGF) during chronic liver disease and hepatocellular transformation. We address the hypothesis that blocking the EGF-EGF receptor (EGFR) pathway may be an effective strategy for inhibiting fibrogenesis and hepatocarcinogenesis. A rat model of diethylnitrosamine (DEN)-induced cirrhosis was used to examine the effects of erlotinib on underlying chronic liver disease and HCC formation. The DEN-induced rat model closely resembles disease progression in humans both pathologically and molecularly. Erlotinib significantly prevented the development of HCC tumor nodules in a dose-dependent fashion. Further, erlotinib inhibited the activation of hepatic stellate cells and prevented fibrogenesis. Erlotinib also reduced hepatotoxicity and improved liver function. Finally, a gene expression signature predictive of poor survival in human cirrhosis patients was reversed in response to erlotinib. Our data demonstrate for the first time that EGFR inhibition prevents liver fibrogenesis. Further, our results suggest that erlotinib is a potentially effective HCC chemoprevention strategy through inhibition of cirrhosis progression which can be monitored at the molecular level. Animals received humane care according to the criteria outlined in the M-bM-^@M-^\Guide for the Care and Use of Laboratory AnimalsM-bM-^@M-^] of the National Academy of Sciences. All animals were maintained in accordance with the institutional guidelines of the Massachusetts General Hospital Subcommittee on Research Animal Care. Male Wistar rats received weekly IP injections of diethylnitrosamine (DEN) at 50 mg/kg, 100mg/kg, or vehicle control (PBS) for 18 weeks. A subset of rats received either daily (5X a week) IP injections of 2 mg/kg erlotinib or vehicle control during weeks 13 - 18. In a separate study, the erlotinib dose was lowered to 0.5 mg/kg. The vehicle groups from the two studies were not significantly different so they were combined together for analysis. Rats were weighed at the end of each week. Animals were sacrificed at 9, 13 and 19 weeks after a one-week washout period to eliminate acute effects of DEN. At the time of sacrifice, the non-tumor liver tissues were collected in RNase-free tubes and snap-frozen in liquid nitrogen. Frozen tissues were stored at -80M-BM-0C until RNA extraction.
2014-02-28 | E-GEOD-27638 | biostudies-arrayexpress
Project description:Gene-expression profiles of liver and hepatocellular carcinoma induced by diethylnitrosamine (DEN) in KLF6 +/- and wild type KLF6 mice. Inactivation of the KLF6 tumor suppressor is common in HCC due to hepatitis C virus (HCV), consistent with its anti-proliferative activity in HCC-derived cell lines and in hepatocytes of transgenic mice. We have evaluated the impact of KLF6 depletion on human HCC and experimental hepatocarcinogenesis. In patients with surgically resected HCC, those with significantly reduced tumor expression of KLF6 had a significantly decreased survival. We modeled this event in KLF6 +/- mice, which displayed significantly more tumorigenicity than KLF6 +/+ animals in response to the hepatic carcinogen DEN, associated with recapitulation of gene signatures in both surrounding tissue and tumors that are associated with aggressive human HCCs. In DNA microarrays, mdm2 mRNA expression was increased in tumors from KLF6 +/- compared to KLF6 +/+ mice, which was validated by realtime qPCR and Western blot in both human HCC and DEN-induced murine tumors. Moreover, chromosomal immunoprecipitation and co-transfection assays established the P2 intronic promoter of mdm2 as a bona fide transcriptional target repressed by KLF6. Whereas KLF6 over-expression in HCC cell lines led to reduced MDM2 levels and increased p53 protein and transcriptional activity, reduction in KLF6 by siRNA led to increased MDM2 and reduced p53. Our findings indicate that KLF6 deficiency contributes significantly to the carcinogenic milieu in human and murine HCC, and uncover a novel tumor suppressor activity of KLF6 in HCC, by linking its transcriptional repression of MDM2 to stabilization of p53. Keywords: Liver, Hepatocellular carcinoma, Expression array, Exon array, Affymetrix
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