Role of metallothionein on carcinogenesis and tumor progression in bladder cancer.

(1)永生化金属硫蛋白缺失细胞：将猴病毒40基因导入金属硫蛋白缺失成纤维细胞，建立永生化金属硫蛋白缺失细胞。另外，建立了永生化对照成纤维细胞。永生化MT细胞对镉的敏感性增加，对锌、铜、汞或镍不敏感。这些结果发表在《生命科学》杂志64、1999、145-150上。(2)金属硫蛋白预防致癌。我们检测了N-丁基-N-(4-羟基丁基)亚硝胺(BBN)在MT I和II基因缺陷转基因小鼠和对照(129/Sv)小鼠中的致癌作用。BBN可诱发75%的MT基因缺失小鼠和43%的129/Sv小鼠发生膀胱癌。MT基因缺失小鼠的平均每只小鼠的膀胱癌数量显著高于129/Sv小鼠。锌处理可抑制BBN对129/Sv小鼠的致癌性，但对MT缺失小鼠的致癌性无明显影响。这些结果发表在《肿瘤发生，20,1999,1625-1627》上。(3)组织病理学检查显示，所有的肿瘤标本都显示出MT基因缺失和129/Sv小鼠移行细胞癌的形态改变。129/Sv小鼠主要膀胱肿瘤呈高级别特征，而MT缺失小鼠无一例肿瘤分级为III级。因此，129/Sv小鼠膀胱肿瘤的恶性潜能大于MT缺失小鼠。MT阴性的膀胱肿瘤细胞不能被镉诱导为MT。这些细胞对镉和顺铂敏感，对129/Sv膀胱肿瘤细胞具有敏感性。

(1) Immortalized metallothionein null cellsImmortalized metallothionein(MT) null cells were established by transfection of simian virus 40 into MT null fibroblast. Additionally, immortalized control fibroblast were established. Immortalized MT null cells showed increased sensitivity cadmium not to zinc, copper, mercury or nickel. These results were written in Life Science, 64,1999,145-150.(2) Metallothionein prevents the carcinogenicity.We examined the carcinogenicity of N-butyl-N-(4-hydroxybutyl) nitrosamine(BBN) in transgenic mice deficient in the MT I and II genes and control (129/Sv) mice. BBN induced bladder tumors in 75% of MT null mice and in 43% of 129/Sv mice. The average number of bladder tumors per mouse was significantly higher in MT null mice than in 129/Sv mice. Zinc treatment suppressed the carcinogenicity of BBN in 129/Sv mice but not in MT null mice. These results were written in Carcinogenesis, 20, 1999, 1625-1627.(3) Histopathologic examinationHistopathologic examination revealed that all tumor samples showed morphological changes characteristic of transitional cell carcinoma in both MT null and 129/Sv mice. The major bladder tumors in 129/Sv mice displayed the features of high grade, whereas none of the tumors in MT null mice were designated as grade III.Thus, the malignant potential of bladder tumors in 129/Sv mice was greater than that in MT null mice.(4) MT null bladder tumor cell lineWe established MT null and 129/Sv bladder tumor cell line. MT null bladder tumor cells were unable to induced MT by administered cadmium. These cells were sensitive to cadmium and cisplatin against 129/Sv bladder tumor cells.