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Overexpression of Glutamine Synthetase Is Associated with ß-Catenin-Mutations in Mouse Liver Tumors during Promotion of Hepatocarcinogenesis by Phenobarbital¹

Institut für Toxikologie, Universität Tübingen, 72074 Tübingen [S. L., D. S., A. B., M. S.]; Institut für Biochemie, Universität Leipzig, 04103 Leipzig [F. G., R. G.]; and Universitäts-Frauenklinik, Universität Tübingen, 72076 Tübingen [R. K.], Germany

Phenobarbital (PB) is an antiepileptic drug that promotes hepatocarcinogenesis in rodents when administered subsequent to an initiating carcinogen like N-nitrosodiethylamine (DEN). In the mouse, the promotional effect of PB on liver tumor development results from a selective stimulation of clonal outgrowth of hepatocytes harboring activating mutations in the ß-catenin gene. Because glutamine synthetase (GS) has recently been shown to be a putative transcriptional target of ß-catenin, expression of GS during PB-mediated promotion of mouse hepatocarcinogenesis was investigated. Preneoplastic and neoplastic liver lesions were induced in 6-week-old male mice by a single injection of 90 µg/g body weight of DEN, and groups of mice were subsequently kept on PB-containing (0.05%) or control diet for 39 weeks. In PB-treated mice, 46 of 51 lesions (90%) were GS-positive in contrast to only 16 of 46 (35%) in mice not treated with PB. Approximately 33% of liver was occupied by neoplastic tissue in PB-treated mice, of which >80% was GS positive. By contrast, only 3.5% of liver consisted of neoplastic tissue in mice treated with DEN only, and 25% of this was GS positive. We have previously shown that ß-catenin mutations are present in 80% of liver tumors from PB-treated mice but are absent in liver tumors from mice treated with DEN only. By analyzing a panel of larger liver tumors, we now observed that tumors harboring ß-catenin mutations were GS positive, whereas tumors without ß-catenin mutations were GS negative. Similarly, tumors from an additional mouse carcinogenicity experiment where PB inhibited rather than promoted hepatocarcinogenesis were mostly GS negative. These data suggest that promotion of hepatocarcinogenesis by PB confers ß-catenin-mutated tumor cells with a selective advantage by up-regulation of GS expression.

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