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ToxSci Advance Access published online on September 1, 2005

Toxicological Sciences, doi:10.1093/toxsci/kfi309
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received July 19, 2005
Accepted August 29, 2005

Carcinogenicity

Use of a Rainbow Trout Oligonucleotide Microarray to Determine Transcriptional Patterns in Aflatoxin B1-Induced Hepatocellular Carcinoma Compared to Adjacent Liver

Susan C. Tilton 1, Lena G. Gerwick 2, Jerry D. Hendricks 3, Caprice S. Rosato 4, Graham Corley-Smith 2, Scott A. Givan 4, George S. Bailey 1, Christopher J. Bayne 2, and David E. Williams 1*

1 Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, OR, 97331; Marine & Freshwater Biomedical Sciences Center, Oregon State University, Corvallis, OR, 97331; The Linus Pauling Institute, Oregon State University, Corvallis, OR, 97331
2 Marine & Freshwater Biomedical Sciences Center, Oregon State University, Corvallis, OR, 97331; Department of Zoology, Oregon State University, Corvallis, OR, 97331
3 Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, OR, 97331; Marine & Freshwater Biomedical Sciences Center, Oregon State University, Corvallis, OR, 97331
4 Center for Gene Research and Biotechnology, Oregon State University, Corvallis, OR, 97331

* To whom correspondence should be addressed.
David E. Williams, E-mail: david.williams{at}oregonstate.edu


   Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and its occurrence is associated with a number of environmental factors including ingestion of the dietary contaminant aflatoxin B1 (AFB1). Research over the last 40 years has revealed rainbow trout (Oncorhynchus mykiss) to be an excellent research model for study of AFB1-induced hepatocarcinogenesis, however little is currently known about changes at the molecular level in trout tumors. We have developed a rainbow trout oligonucleotide array containing 1,672 elements representing over 1,400 genes of known or probable relevance to toxicology, comparative immunology, carcinogenesis, endocrinology and stress physiology. In this study, we applied microarray technology to examine gene expression of AFB1-induced HCC in the rainbow trout tumor model. Carcinogenesis was initiated in trout embryos with 50 ppb AFB1 and after 13 months control livers, tumors and tumor-adjacent liver tissues were isolated from juvenile fish. Global gene expression was determined in histologically confirmed HCCs compared to non-cancerous adjacent tissue and sham-initiated control liver. We observed distinct gene regulation patterns in HCC compared to non-cancerous tissue including upregulation of genes important for cell cycle control, transcription, cytoskeletal formation and the acute phase response and down regulation of genes involved in drug metabolism, lipid metabolism and retinol metabolism. Interestingly, the expression profiles observed in trout HCC are similar to the transcriptional signatures found in human and rodent HCC further supporting the validity of the model. Overall, these findings contribute to a better understanding of the mechanism of AFB1-induced hepatocarcinogenesis in trout and identify conserved genes important for carcinogenesis in species separated evolutionarily by more than 400 million years.

Keywords: hepatocellular carcinoma; aflatoxin B1; rainbow trout; oligonucleotide microarray; gene regulation.
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