Carcinogenesis Advance Access originally published online on June 26, 2008
Carcinogenesis 2008 29(11):2218-2226; doi:10.1093/carcin/bgn135
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Cellular distributions of molecules with altered expression specific to the tumor promotion process from the early stage in a rat two-stage hepatocarcinogenesis model
1 Division of Pathology
2 Division of Molecular Toxicology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
3 Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu City, Tokyo 183-8509, Japan
4 Food Safety Commission, 2-13-10 Prudential Tower 6th Floor, Nagata-cho, Chiyoda-ku, Tokyo 100-8989, Japan
* To whom correspondence should be addressed. Tel: +81 42 367 5874; Fax: +81 42 367 5771; Email: mshibuta{at}cc.tuat.ac.jp
A global gene expression profiling specific to the early process of tumor promotion by fenbendazole (FB) or phenobarbital (PB) in a rat two-stage hepatocarcinogenesis model revealed 33 genes to show altered expression in common with both chemicals. The immunohistochemical distribution of transferrin receptor (Tfrc), nuclear receptor subfamily 0, group B, member 2 (Nr0b2) and minichromosome maintenance deficient 6 (MCM6), included in the altered expression profile, were therefore examined in FB- and PB-induced proliferative lesions at both early and late stages of tumor promotion. In addition, immunoexpression of transforming growth factor β receptor (TGFβR) I, TGFβRII, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and phosphorylated phosphatase and tensin homolog deleted on chromosome 10 (pPTEN) was also examined. In the early stage, most hepatocellular foci positive for glutathione S-transferase placental form (GST-P) showed co-expression of TGFβRI and lack of PTEN and pPTEN, some GST-P-positive foci co-expressing Tfrc and Nr0b2. In the late stage, selective expression of TGFβRI, but not TGFβRII, was also observed in many adenomas and carcinomas consistently expressing GST-P. Nr0b2 was variably expressed in the proliferative lesions, irrespective of the carcinogenic stage. Like the GST-P-positive foci, adenomas and carcinomas consistently lacked PTEN and pPTEN. Expression of Tfrc and MCM6 was increased in parallel with the carcinogenic stage. In conclusion, loss of PTEN and dysregulation of transforming growth factor β signaling can be considered to be involved in rat hepatocarcinogenesis from early stages. Selective expression of Tfrc in proliferative lesions suggests an involvement of changes in iron homeostasis during the process of tumor promotion/progression driven by FB or PB.
Abbreviations: CYP, cytochrome P450; DEN, N-diethylnitrosamine; FB, fenbendazole; GST-P, glutathione S-transferase placental form; MCM6, minichromosome maintenance deficient 6; Nr0b2, nuclear receptor subfamily 0, group B, member 2; PH, partial hepatectomy; PB, phenobarbital; PTEN, phosphatase and tensin homolog deleted on chromosome 10; pPTEN, phosphorylated phosphatase and tensin homolog deleted on chromosome 10; RT, reverse transcription; PCR, polymerase chain reaction; Tfrc, transferrin receptor; TGF, transforming growth factor; TGFβR, transforming growth factor β receptor
Received February 23, 2008; revised May 17, 2008; accepted May 25, 2008.