Differential expression in DEN/CCl4-induced HCC upon the genetic absence of Autotaxin (ATX) in hepatocytes
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Vassilis Aidinis
PROVIDER: E-MTAB-4648 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:The effect of Tlr4P712H mutation (rendering TLR4 non-functional), or gut-sterilization by antbiotics, on the induction of tumorgenesis by CCl4 and diethylnitrosamine (DEN) was characterized. Affymetrix Mouse 430 2.0 gene expression measurements were used to characterize the transcriptomic basis of the effects of the above treatments and genotypes on tumorgenesis. Gene expression of mouse livers of A. Normal liver from WT C3H/HeOuJ mice, B. HCC from WT C3H/HeOuJ mice treated with CCl4 and DEN, C.HCC from TLR4-mutant C3H/HeJ mice (Tlr4P712H) treated with CCl4 and DEN and D.HCC from WT C3H/HeOuJ mice treated with antibiotics (a combination of ampicillin (1 g/l), neomycin [1 g/l], metronidazole[1 g/l] and vancomycin [500 mg/l] in drinking water) and CCl4 and DEN were characterized.
2013-01-03 | E-GEOD-33446 | biostudies-arrayexpress
Project description:The effect of Tlr4P712H mutation (rendering TLR4 non-functional), or gut-sterilization by antibiotics, on the induction of tumorgenesis by CCl4 and diethylnitrosamine (DEN) was characterized. Affymetrix Mouse 430 2.0 gene expression measurements were used to characterize the transcriptomic basis of the effects of the above treatments and genotypes on tumorgenesis. Gene expression of mouse livers of A. WT C3H/HeOuJ mice, B. WT C3H/HeOuJ mice treated with CCl4 and DEN, C. TLR4-mutant C3H/HeJ mice (Tlr4P712H) treated with CCl4 and DEN and D. WT C3H/HeOuJ mice treated with antibiotics (a combination of ampicillin (1 g/l), neomycin [1 g/l], metronidazole[1 g/l] and vancomycin [500 mg/l] in drinking water) and CCl4 and DEN were characterized.
2014-07-04 | E-GEOD-30485 | biostudies-arrayexpress
Project description:Hepatocellular carcinoma (HCC) is a prevalent human cancer with rising incidence worldwide. Human HCC is frequently associated with chronic liver inflammation and cirrhosis, pathophysiological processes that are a consequence of chronic viral infection, disturbances in metabolism, or exposure to chemical toxicants. To better characterize the pathogenesis of HCC, we used a human disease-relevant mouse model of fibrosis-associated hepatocarcinogenesis. In this model, marked liver tumor response caused by a pro-mutagenic chemical N-nitrosodiethylamine in presence of liver fibrosis was associated with epigenetic events indicative of genomic instability. Therefore, we hypothesized that DNA copy number alterations (CNAs), a feature of genomic instability and a common characteristic of cancer, are concordant between human HCC and mouse models of fibrosis-associated hepatocarcinogenesis. We evaluated DNA CNAs and changes in gene expression in the mouse liver (normal, tumor and non-tumor cirrhotic tissues). In addition, we compared our findings to those in human HCC (tumor and non-tumor cirrhotic/fibrotic tissues). We observed that while fibrotic liver tissue is largely devoid of DNA CNAs, highly frequently occurring DNA CNAs are found in mouse tumors, which is indicative of a profound increase in chromosomal instability in HCC. When compared to CNAs in human HCC, we found that 33% of genes in these segments are similarly affected in the mouse tumors. Our results suggest that CNAs most commonly arise in neoplastic tissue rather than in fibrotic liver, and demonstrate the utility of this mouse model in replicating the molecular features of human HCC. Genomic DNA was extracted from frozen liver samples from vehicle-control and DEN+CCl4-treated mice using a DNEasy kit (Qiagen, Valencia, CA). Eighteen mouse tumor samples were included in the study, as well as 18 matched non-tumor samples taken from fibrotic, non-tumorous, surrounding liver tissue from the same mice. Liver DNA from 6 vehicle control-mice was pooled and used as the reference genome in the aCGH experiments. Copy number alterations were identified using the normalized data.
2015-11-01 | E-GEOD-71849 | biostudies-arrayexpress
Project description:Gene-expression profiles of liver tissue of cabon tetrachloride (CCl4)-treated mouse 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. Strain A/J male mice (Jackson Laboratory, Bar Harbor, ME) were treated three times a week for 18 weeks with either 0.1cc of a 40 percent solution of CCl4 (Sigma) in olive oil or with vehicle control by oral gavage. Mice were sacrificed at 19 weeks after a one-week washout to eliminate acute effects of CCl4. The liver was sectioned and fixed in phosphate-buffered 10% formaldehyde for histological analysis. The remaining portions of the liver were collected in RNase-free tubes and snap-frozen in liquid nitrogen. Frozen tissues were stored at -80M-BM-0C until use.
2014-02-28 | E-GEOD-27640 | biostudies-arrayexpress
Project description:The diethylnitrosamine HCC rat model (DEN-HCC) is a useful preclinical model mirroring human hepatocellular carcinoma. To overcome tumor heterogeneity of human HCCs linked to different etiologies and clonal selection, rat HCC samples were compared with matched non-tumor livers in order to identify HCC-related genes involved in the carcinogenetic process. Specifically, male Wistar rats received DEN (Sigma-Aldrich) in the drinking water (100 mg/L) for 8 weeks. Two weeks later the end of DEN treatment, animals were monitored by ultrasound imaging. Animals were euthanized 1 or 2 months after the end of DEN treatment, when the major diameter of at least one HCC nodule reached a dimension of 10 mm. Samples were collected for molecular biology and total RNA for microarray analysis was extracted by using Trizol. Two rat livers from untreated mice were included in the analysis.
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Project description:To decipher the role of Enpp2 (ATX) in lung carcinogenesis, a replication-deficient adenovirus expressing the cre recombinase (Ad-Cre) was administered intratracheally to K-rasLSL-G12D/+Enpp2n/n mice, as well as to control K-rasLSL-G12D/+ littermates, thus removing the synthetic stop element (LSL; lox-stop-lox) and allowing the expression of the oncogene and the overtime development of LC, as well as the genetic deletion of enpp2 in the corresponding mice. RNA was extracted from 3 lung samples per genotype and hybriidized to Affy microarrays.
2018-08-30 | E-MTAB-6706 | biostudies-arrayexpress
Project description:Lysophosphatidic acid (LPA) acts through high-affinity G protein-coupled receptors to mediate a plethora of physiological and pathological activities associated with tumorigenesis. LPA receptors and autotaxin (ATX/LysoPLD), the primary enzyme producing LPA, are aberrantly expressed in multiple cancer lineages. However, the role of ATX and LPA receptors in the initiation and progression of breast cancer has not been evaluated. We demonstrate that expression of ATX or each edg family LPA receptor in mammary epithelium of transgenic mice is sufficient to induce a high frequency of late-onset, estrogen receptor (ER)-positive, invasive, and metastatic mammary cancer. Thus, ATX and LPA receptors can contribute to the initiation and progression of breast cancer.
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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:Brown adipose tissue (BAT) is a thermogenic organ that dissipates stored energy as heat to maintain body temperature in infants and small mammals. This process may also provide protection from development of diet-induced obesity. We found that the bioactive lipid mediator lysophosphatidic acid (LPA) markedly decreases differentiation of cultured primary brown adipocyte precursors, while potent selective inhibitors of the LPA-generating enzyme autotaxin (ATX) promote differentiation. Transgenic mice overexpressing ATX exhibited reduced expression of BAT-related genes in peripheral white adipose tissue and accumulated significantly more fat than wild-type controls when fed a high fat diet. Our results indicate that ATX and its product LPA are physiologically relevant negative regulators of brown fat adipogenesis and suggest that a decrease in peripheral brown adipose tissue results in increased susceptibility to diet-induced obesity in mice.
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