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ORIGINAL RESEARCH ARTICLE

T Cell Deficiency Leads to Liver Carcinogenesis in Azoxymethane-Treated Rats

Bin Wu^*, Akifumi Ootani^*,1,2, Ryuichi Iwakiri^*, Yasuhisa Sakata^*, Takehiro Fujise^*, Sadahiro Amemori^*, Fumie Yokoyama^*, Seiji Tsunada^*, Shuji Toda and Kazuma Fujimoto^*

^* Department of Internal Medicine and Department of Pathology, Saga Medical School, Saga, Japan

To whom requests for reprints should be addressed at ¹ Department of Internal Medicine, Saga Medical School, 5–1–1 Nabeshima, Saga 849-8501, Japan. E-mail: aootani{at}stanford.edu

There is an increasing amount of evidence suggesting that T cell deficiency contributes to tumor development. However, it is unclear whether T cell deficiency leads to liver and colon carcinogenesis. The aim of this study was to investigate the role of T cells on liver and colon carcinogenesis. Athymic F344/N Jcl-rnu/– (nu/nu) rats and euthymic F344/N Jcl-rnu/+(nu/+) rats were administered the carcinogen azoxymethane (AOM) at a dose of 15 mg/kg body wt once a week for 2 weeks. At 48 weeks after the second carcinogen treatment, the rats were sacrificed, and livers and colons were examined. Apoptosis and cell proliferation were evaluated by DNA fragmentation and proliferating cell nuclear antigen assays, respectively. Wild-type p53 and members of the Jun and Fos oncogene families were detected by Western blotting. AOM treatment induced 100% liver tumor and 63.6% colon tumor incidence in T cell–deficient nu/nu rats, compared with 0% and 38.5% incidence in nu/+ rats. T cell deficiency promoted the inhibitory action of AOM on apoptosis in both liver and colon at 48 weeks. In contrast, T cell deficiency increased cell proliferation after AOM treatment in both tissues. Wild-type p53 was reduced in both tissues of T cell–deficient rats. AOM treatment induced c-Jun and c-Fos expressions in the liver but increased only Fos B in the colon, whereas T cell deficiency enhanced c-Jun overexpression in the liver. These results suggest that T cell deficiency leads to liver carcinogenesis partly by a reduction in wild-type p53 and increasing c-Jun expression in AOM-treated rats.

Key Words: carcinogenesis • liver • colon • wt p53 • Jun oncogene family • Fos oncogene family