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Gene expression in trout hepatocellular carcinoma

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). While etiology of the disease is relatively well defined, the molecular mechanisms of tumorigenesis are poorly understood. In this study, we examined, for the first time, gene expression of AFB1-induced HCC by microarray in the rainbow trout (Oncorhynchus mykiss) tumor model. Carcinogenesis was initiated in trout embryos with 50 ppb AFB1 and 13 months later 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 utilizing a rainbow trout oligonucleotide array containing approximately 1500 genes of known or probable relevance to toxicology, comparative immunology, carcinogenesis and stress physiology. 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. These gene classes have previously been observed to be important in the regulation of HCC in human and rodent models. Overall, these findings contribute to a better understanding of the mechanism of AFB1-induced hepatocarcinogenesis in the trout model and identify conserved genes important for carcinogenesis in species separated evolutionarily by more than 400 million years. Keywords: other

ORGANISM(S): Oncorhynchus mykiss

PROVIDER: GSE2686 | GEO | 2005/09/06

SECONDARY ACCESSION(S): PRJNA92191

REPOSITORIES: GEO

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Project description:Background: Previously, we reported that perfluorooctanoic acid (PFOA) promotes liver cancer in manner similar to that of 17β-estradiol (E2) in rainbow trout. Also, other perfluoroalkyl acids (PFAAs) are weakly estrogenic in trout and bind the trout liver estrogen receptor (ER). Objectives: The primary objective of this study was to determine whether multiple PFAAs enhance hepatic tumorigenesis in trout, an animal model that represents human insensitivity to peroxisome proliferators. Methods: A two-stage chemical carcinogenesis model was employed in trout to evaluate PFOA, perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluorooctane sulfonate (PFOS) and 8:2 fluorotelomer alcohol (8:2FtOH) as complete carcinogens or promoters of aflatoxin B1 (AFB1)- and/or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced liver cancer. A custom trout DNA microarray was used to assess hepatic transcriptional response to these dietary treatments in comparison to E2 and the classic peroxisome proliferator clofibrate (CLOF). Results: Incidence, multiplicity and size of liver tumors in trout fed diets containing E2, PFOA, PFNA and PFDA were significantly higher compared to AFB1-initiated animals fed control diet, whereas PFOS caused a minor increase in liver tumor incidence. E2 and PFOA also enhanced MNNG-initiated hepatocarcinogenesis. Pearson correlation analyses, unsupervised hierarchical clustering and principal components analyses showed that the hepatic gene expression profiles for E2 and PFOA, PFNA, PFDA and PFOS were overall highly similar, though distinct patterns of gene expression were evident for each treatment, particularly for PFNA. Conclusions: Overall, these data suggest that multiple PFAAs can promote liver cancer and that the mechanism of promotion may be similar to that for E2. A total of 40 samples were analyzed using a a dye-swap, reference sample hybridization protocol. Rainbow trout were exposed to the following experimental treatments via the diet for two weeks (number in parenthesis is assigned group #): (1) Control; (2) 5 mg/kg diet estradiol (E2); (3) 2000 mg/kg diet perfluorooctanoic acid (PFOA); (4) 2000 mg/kg diet perfluorononanoic acid (PFNA); (5) 2000 mg/kg diet perfluorodecanoic acid (PFDA); (6) 200 mg/kg diet perfluorooctane sulfonate; (7) 2000 mg/kg 8:2 fluorotelomer alcohol (FTOH); and (8) 2000 mg/kg diet clofibrate. A total of 40 total hepatic mRNA samples were analyzed using a dye-swap, reference sample hybridization protocol. A reference RNA pool was made by combining equal amounts of RNA from all control RNA samples, with one exception. A separate time-matched reference pool was utilized for group 6 samples (PFOS treatment). Five hybridizations were performed for each treatment group in the following pattern: Replicate A Cy5/Reference Cy3; Replicate A Cy3/Reference Cy 5; Replicate B Cy5/Reference Cy3; Replicate B Cy3/Reference Cy5; Replicate C Cy5/Reference Cy3. Thus, the experiment consisted of three biological replicates, for two of which were replicated technically.

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Gene expression in trout hepatocellular carcinoma

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