Ilic Zoran, Mondal Tapan K, Guest Ian, Crawford Dana R, Sell Stewart
1 Wadsworth Center, New York State Department of Health, Albany, NY, USA.
2 Albany Medical College, Albany, NY, USA.
Tumour Biol. 2018 May;40(5):1010428318777344. doi: 10.1177/1010428318777344.
Aflatoxin B, arguably the most potent human carcinogen, induces liver cancer in humans, rats, trout, ducks, and so on, but adult mice are totally resistant. This resistance is because of a detoxifying enzyme, mouse glutathione S-transferase A3, which binds to and inactivates aflatoxin B epoxide, preventing the epoxide from binding to DNA and causing mutations. Glutathione S-transferase A3 or its analog has not been detected in any of the sensitive species, including humans. The generation of a glutathione S-transferase A3 knockout (represented as KO or -/-) mice has allowed us to study the induction of liver cancer in mice by aflatoxin B. In contrast to the induction of hepatocellular carcinomas in other species, aflatoxin B induces cholangiocarcinomas in GSTA3-/- mice. In other species and in knockout mice, the induction of liver cancer is preceded by extensive proliferation of small oval cells, providing additional evidence that oval cells are bipolar stem cells and may give rise to either hepatocellular carcinoma or cholangiocarcinoma depending on the nature of the hepatocarcinogen and the species of animal. The recent development of mouse oval cell lines in our laboratory from aflatoxin B-treated GSTA3-/- mice should provide a new venue for study of the properties and potential of putative mouse liver stem cells.
黄曲霉毒素B可谓是最具威力的人类致癌物，可在人类、大鼠、鳟鱼、鸭子等动物中诱发肝癌，但成年小鼠却完全具有抗性。这种抗性源于一种解毒酶——小鼠谷胱甘肽S-转移酶A3，它能与黄曲霉毒素B环氧化物结合并使其失活，从而防止环氧化物与DNA结合并导致突变。在包括人类在内的任何敏感物种中均未检测到谷胱甘肽S-转移酶A3或其类似物。谷胱甘肽S-转移酶A3基因敲除（表示为KO或-/-）小鼠的产生，使我们能够研究黄曲霉毒素B对小鼠肝癌的诱发作用。与在其他物种中诱发肝细胞癌不同，黄曲霉毒素B在GSTA3-/-小鼠中诱发胆管癌。在其他物种和基因敲除小鼠中，则是先出现小卵圆细胞的广泛增殖，然后才诱发肝癌，这进一步证明卵圆细胞是双潜能干细胞，并且可能根据肝癌致癌物的性质和动物物种的不同，分化为肝细胞癌或胆管癌。最近，我们实验室从经黄曲霉毒素B处理的GSTA3-/-小鼠中培育出了小鼠卵圆细胞系，这应为研究假定的小鼠肝干细胞的特性和潜能提供一个新的途径。
