Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of rodent hepatic carcinogenesis

ABSTRACT: 3 dose levels of each of 9 compounds were used to dose male SD rats q.d. by oral gavage. Compounds included 5 nongenotoxic carcinogens (bemitradine, clofibrate, doxylamine, methapyrilene, & phenobarbital), 2 genotoxic agents (tamoxifen and 2-AAF) and 2 non-carcinogens (4-AAF and isoniazid). This work has been described in Kramer JA, Curtiss SW, Kolaja KL, Alden CA, Blomme EAG, Curtiss WC, Davila JC, Jackson CJ, and Bunch RT. (2004) Acute Molecular Markers of Rodent Hepatic Carcinogenesis Identified by Transcription Profiling. Chem. Res. Toxicol., in press.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Jeffrey Kramer

PROVIDER: E-MEXP-89 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Acute molecular markers of rodent hepatic carcinogenesis identified by transcription profiling.

Kramer Jeffrey A JA Curtiss Sandra W SW Kolaja Kyle L KL Alden Carl L CL Blomme Eric A G EA Curtiss William C WC Davila Julio C JC Jackson Carmen J CJ Bunch Roderick T RT

Chemical research in toxicology 20040401 4

Currently, the only way to identify nongenotoxic hepatocarcinogens is through long-term repeat dose studies such as the 2 year rodent carcinogenicity assay. Such assays are both time consuming and expensive and require large amounts of active pharmaceutical or chemical ingredients. Thus, the results of the 2 year assay are not known until very late in the discovery and development process for new pharmaceutical entities. Although in many cases nongenotoxic carcinogenicity in rodents is considere ...[more]

PMID: 15089088

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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.

Project description:The adult skeletal muscle is a plastic tissue with a remarkable ability to adapt to different levels of activity by altering its excitability, its contractile and metabolic phenotype and its mass. Knowledge on the mechanisms responsible for muscle mass comes primarily from models of muscle inactivity or denervation or from genetic models of muscle diseases. Given that the underlying exercise-induced transcriptional mechanisms regulating muscle mass are not fully understood, here we investigated the cellular and molecular adaptive mechanisms taking place in fast skeletal muscle of adult zebrafish in response to swimming. Fish were trained at low swimming speed (0.1 m/s; non-exercised) or at their optimal swimming speed (0.4 m/s; exercised). A significant increase in fibre cross-sectional area (1,290 M-BM-1 88 vs. 1,665 M-BM-1 106 M-NM-<m2) and vascularization (298 M-BM-1 23 vs. 458 M-BM-1 38 capillaries/mm2) was found in exercised over non-exercised fish. Gene expression profiling evidenced the transcriptional activation of a series of complex networks of extracellular and intracellular signaling molecules and pathways involved in the regulation of muscle mass, myogenesis and angiogenesis, many (e.g. BMP, TGFM-oM-^AM-", FGF, Notch, Wnt, MEF2, Shh, EphrinB2) not previously associated with exercise-induced contractile activity, and that recapitulate in part the transcriptional events occurring during skeletal muscle regeneration. These results demonstrate that fibre hypertrophy is responsible for the growth-promoting effects of exercise accompanied by a switch to a more oxidative capacity of white muscle fibres to fuel the increased energy demands. Importantly, our study identified novel molecular mechanisms regulating muscle mass and function in vertebrates. Adult zebrafish were subjected or not to a swim training regime consisting of swimming at the optimal swimming speed for this species for 6 h/day, 5 days/week for a total of 4 weeks (20 experimental days). Total RNA of fast muscle from individual non-exercised (n = 8) and exercised (n = 8) zebrafish was analyzed.

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Transcription profiling of rodent hepatic carcinogenesis

Publications

Acute molecular markers of rodent hepatic carcinogenesis identified by transcription profiling.

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