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The expression of gamma-glutamyltranspeptidase (gamma-GTP) and the relationship between this enzyme activity and tumorigenicity were studied in 38 tumorigenic and non-tumorigenic epithelial cell lines derived from livers of normal and aminoazo-dye-fed rats. Nine of 22 non-tumorigenic epithelial cell lines exhibited gamma-GTP-positive cells, whereas 9 of 16 tumorigenic epithelial cell lines did not exhibit gamma-GTP-positive cells. This finding revealed that no correlation existed between the acquisition of gamma-GTP activity and tumorigenicity. None of 10 spontaneously transformed epithelial cell lines, which consisted of 8 tumorigenic and 2 non-tumorigenic cell lines, exhibited gamma-GTP-positive cells. On the other hand, 16 of 28 transformed epithelial cell lines, which were derived from aminoazo-dye-fed rat livers and aminoazo-dye-treated cultures of normal rat liver cells, included gamma-GTP-positive cells in various percentages. As described above, in contrast to in vitro spontaneous transformation of rat liver cells, it is obvious that the carcinogen-induced transformation of rat liver cells in vitro as well as in vivo was frequently accompanied by the acquisition of gamma-GTP-activity. Therefore, it is concluded that the expression of gamma-GTP in liver cells may be mainly associated with exposure to chemical carcinogens.
The expression of gamma-glutamyltranspeptidase (gamma-GTP) and the relationship between this enzyme activity and tumorigenicity were studied in 38 tumorigenic and non-tumorigenic epithelial cell lines derived from livers of normal and aminoazo-dye-fed rats. Nine of 22 non-tumorigenic epithelial cell lines exhibited gamma-GTP-positive cells, whereas 9 of 16 tumorigenic epithelial cell lines did not exhibit gamma-GTP-positive cells. This finding revealed that no correlation existed between the acquisition of gamma-GTP activity and tumorigenicity. None of 10 spontaneously transformed epithelial cell lines, which consisted of 8 tumorigenic and 2 non-tumorigenic cell lines, exhibited gamma-GTP-positive cells. On the other hand, 16 of 28 transformed epithelial cell lines, which were derived from aminoazo-dye-fed rat livers and aminoazo-dye-treated cultures of normal rat liver cells, included gamma-GTP-positive cells in various percentages. As described above, in contrast to in vitro spontaneous transformation of rat liver cells, it is obvious that the carcinogen-induced transformation of rat liver cells in vitro as well as in vivo was frequently accompanied by the acquisition of gamma-GTP-activity. Therefore, it is concluded that the expression of gamma-GTP in liver cells may be mainly associated with exposure to chemical carcinogens.
Cell cycle checkpoints are barriers to carcinogenesis as they function to maintain genomic integrity. Attenuation or ablation of checkpoint function may enhance tumor formation by permitting outgrowth of unstable cells with damaged DNA. To examine the function of cell cycle checkpoints in rat hepatocarcinogenesis, we analyzed the responses of the G (1), G (2) and mitotic spindle assembly checkpoints in normal rat hepatocytes, hepatic epithelial stem-like cells (WB-F344) and transformed derivatives of both. Normal rat hepatocytes (NRH) displayed a 73% reduction in the fraction of nuclei in early S-phase 6-8 h following 8 Gy of ionizing radiation (IR) as a quantitative measure of G (1) checkpoint function. Chemically and virally transformed hepatocyte lines displayed significant attenuation of G (1) checkpoint function, ranging from partial to complete ablation. WB-F344 rat hepatic epithelial cell lines at low, mid and high passage levels expressed G (1) checkpoint function comparable with NRH. Only one of four malignantly transformed WB-F344 cell lines displayed significant attenuation of G (1) checkpoint function. Attenuation of G (1) checkpoint function in transformed hepatocytes and WB-F344 cells was associated with alterations in p53, ablated/attenuated induction of p21 (Waf1) by IR, as well as aberrant function of the spindle assembly checkpoint. NRH displayed 93% inhibition of mitosis 2 h after 1 Gy IR as a quantitative measure of G (2) checkpoint function. All transformed hepatocyte and WB-F344 cell lines displayed significant attenuation of the G (2) checkpoint. Moreover, the parental WB-F344 line displayed significant age-related attenuation of G (2) checkpoint function. Abnormalities in the function of cell cycle checkpoints were detected in transformed hepatocytes and WB-F344 cells at stages of hepatocarcinogenesis preceding tumorigenicity, sustaining a hypothesis that aberrant checkpoint function contributes to carcinogenesis.
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