J Vet Sci.  2006 Sep;7(3):211-216. 10.4142/jvs.2006.7.3.211.

Altered expression of thioredoxin reductase-1 in dysplastic bile ducts and cholangiocarcinoma in a hamster model

• Yoon BI
• Kim DY
• Jang JJ
• Han JH

• KMID: 1089903
• DOI: http://doi.org/10.4142/jvs.2006.7.3.211

Abstract

Thioredoxin reductase 1 (TrxR) is a homodimeric selenoenzyme catalyzing thioredoxin (Trx) in an NADPHdependent manner. With regard to carcinogenesis, these redox proteins have been implicated in cell proliferation, transformation and anti-apoptosis. In the present study, using a hamster cholangiocarcinoma (ChC) model, we evaluated the immunohistochemical expression pattern of TrxR in precancerous lesions and ChCs as well as in normal bile ducts. The goal of this study was to determine the potential role and importance of TrxR in cholangiocarcinogenesis. For the ChC model, we obtained liver tissue specimens with dysplastic bile ducts prior to the development of ChC 8 weeks after initiation of the experiment and ChC samples at 27 weeks. The immunohistochemical analysis showed diffuse cytoplasmic overexpression of TrxR in the dysplastic bile duct epithelial cells as well as in cholangiocarcinoma; this was comparable to the negative or weakly positive in normal and type 1 hyperplastic bile ducts. However, TrxR appeared to be considerably down-regulated in the ChCs when compared to the higher expression observed in the dysplastic bile ducts. Therefore, these results suggest that TrxR overexpression followed by down-regulation might be an important event in cholangiocarcinogenesis, especially at early stages including the cellular transformation of candidate bile ducts. Further studies are however required to determine whether TrxR may be a potential target molecule for chemoprevention against cholangiocarcinogenesis. In addition, the molecular mechanism as well as the importance of the loss of TrxR in the development of cholangiocarcinoma, following dysplastic transformation of bile duct cells, also remains to be clarified.

Keyword

cholangiocarcinoma; dysplastic bile duct; hamster; thioredoxin reductase-1

MeSH Terms

Animals
Bile Duct Neoplasms/*enzymology/pathology
Bile Ducts/enzymology/pathology
Cholangiocarcinoma/*enzymology/pathology
Cricetinae
Disease Models, Animal
Immunohistochemistry
Mesocricetus
Precancerous Conditions/*enzymology/pathology
Thioredoxin Reductase (NADPH)/*biosynthesis

Figure

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  Fig. 1 Experimental protocol. For the hamster cholangiocarcinoma model, 15 metacercariae of Clonorchis sinensis were used for infection one day before initiating DMN treatment. ChC: Cholangiocarcinoma.

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  Fig. 2 Microphotographs of the liver. A and a, normal bile duct; B and b, type 1 hyperplastic bile ducts; C and c, dysplastic bile ducts. Dysplastic bile ducts and large hyperplastic bile ducts showed strong immunoreactivity for TrxR, while normal (arrow in a) and type 1 hyperplastic bile duct cells (arrow in b) were negative or weakly positive. Dysplastic bile ducts were composed of transformed multi-layered bile duct cells forming irregular lumina. A, B, C; H&E stain, a, b, c; immunohistochemistry for the TrxR. bars = 25 µm.

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  Fig. 3 Microphotographs of cholangiocarcinomas that developed in the hamster model. A and a, tubular type; B and b, tubulocystic type; C and c, undifferentiated type. Immunoreactivity of cholangiocarcinomas for TrxR was down-regulated compared to dysplastic bile ducts (c in Fig. 2); however, it was still much higher than in the normal and type 1 hyperplastic bile duct cells. Expression of TrxR was independent of the classified ChC types except for the undifferentiated type. The neoplastic cells of the undifferentiated type (arrow in C) totally lost TrxR immunoreactivity (arrows in c). A, B, C; H&E stain, bars = 50 µm; a, b, c; immunohistochemistry for TrxR, bars = 25 µm.

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