Significance of overexpression of metallothionein in mouse urinary bladder focal lesions induced by treatment with N‐butyl‐N‐(4‐hydroxybutyl)‐nitrosamine

Abstract

Metallothionein (MT) is expressed in various types of human tumors, including transitional cell carcinomas of the urinary bladder, but its biological significance remains unclear. In the present study, the role of MT in urinary bladder carcinogenesis induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) treatment was investigated using C57BL/6 mice. One hundred 5-week-old male C57BL/6 mice were divided into two groups, which were given drinking water with or without 0.05% BBN throughout the experimental period. Subgroups of ten animals from each group were sacrificed at weeks 5, 10, 15, 20 and 25, and urinary bladder samples were examined immunohistochemically for MT, proliferating cell nuclear antigen (PCNA) and apoptosis. MT was found to be abundant in normal-looking mucosa, but decreased with progression from precancerous lesions to invasive carcinoma in the urinary bladder obtained from BBN-treated mice. Lesions could be divided into MT-positive and negative. There was a tendency for greater MT expression in PCNA-positive lesions, while apoptosis was rather associated with MT-negativity. These data suggest that the overexpression of MT may play a role in mouse urinary bladder carcinogenesis. (Cancer Sci 2003; 94: 1052-1058 etallothionein (MT) is a ubiquitous, low-molecularweight protein with high contents of cysteine and metals, including cadmium, zinc and copper. It is expressed in a wide variety of organisms from yeast to human and is observed in most vertebrate tissues, being localized in both cytoplasm and nuclei of cells.1) Its biosynthesis can be induced by a number of factors, including heavy metals, various cytokines, growth factors, tumor promoters, glucocorticoid hormones and xenobiotics.2) However, the physiological significance of MT is not yet well understood, although its ability to sequester and dispense metal ions is thought to be important for regulation of cellular homeostasis and the functions of essential trace elements such as Zn and Cu, as well as in protection against toxicity of heavy metals, particularly cadmium.3) In addition, MT appears to promote the resistance of cells to not only some alkylating agents and chemotherapeutic metal compounds, such as cisplatin, chlorambucil and melphalan, 4) but also electrophilic mutagens such as N-methyl-N′-nitro-N-nitrosoguanidine and N-methyl-N-nitrosourea. 5) Interestingly, MT has also been implicated in protection against the cytotoxic effects of oxidative stress, because it is a potent hydroxyl radical scavenger.6) In vitro, MT protects cells against the cytotoxic and DNA-damaging effects of nitric oxide and the DNA-damaging effects of H 2 O 2 , 7) and also against radical-induced lipid peroxidation.8) It contributes to metalloregulation during cell growth and differentiation. 9)High levels of MT gene expression have been detected during the late stages of gestation and in the neonatal period.10) Enhanced synthesis of MT in rapidly proliferating tissues appears to suggest a link with cell growth. 4)In humans, functional MT isoforms are enco...

Modulation of Gene Expression in Precancerous Rat Esophagus by Dietary Zinc Deficit and Replenishment

“…Metallothionein overexpression in ESCC is often positively correlated with the metastatic and proliferative activities of the cancer (36). In animal tumor models, overexpression of metallothionein has been shown in chemically induced rat and mouse bladder tumors (39,40). Our results show that metallothionein overexpression occurs in precancerous zinc-deficient esophagus (Tables 1 and 2; Fig.…”

The two faces of metallothionein in carcinogenesis: photoprotection against UVR-induced cancer and promotion of tumour survival

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Chemoprevention of mouse urinary bladder carcinogenesis by fermented brown rice and rice bran

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