Biochemistry of Micronutrients Department, German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany.
Ann N Y Acad Sci. 2012 Jul;1259:19-25. doi: 10.1111/j.1749-6632.2012.06574.x.
Mammalian glutathione peroxidases (GPxs) are reviewed with emphasis on the role of the gastrointestinal GPx2 in tumorigenesis. GPx2 ranks high in the hierarchy of selenoproteins, corroborating its importance. Colocalization of GPx2 with the Wnt pathway in crypt bases of the intestine and its induction by Wnt signals point to a role in mucosal homeostasis, but GPx2 might also support tumor growth when increased by a dysregulated Wnt pathway. In contrast, the induction of GPx2 by Nrf2 activators and the upregulation of COX2 in cells with a GPx2 knockdown reveal inhibition of inflammation and suggest prevention of inflammation-mediated carcinogenesis. The Janus-faced role of GPx2 has been confirmed in a mouse model of inflammation-associated colon carcinogenesis (AOM/DSS), where GPx2 deletion increased inflammation and consequently tumor development, but decreased tumor size. The model further revealed a GPx2-independent decrease in tumor development by selenium (Se) and detrimental effects of the Nrf2-activator sulforaphane in moderate Se deficiency.
哺乳动物谷胱甘肽过氧化物酶 (GPx) 被综述，重点是胃肠道 GPx2 在肿瘤发生中的作用。GPx2 在硒蛋白的层次结构中排名很高，这证明了它的重要性。GPx2 与肠道隐窝底部的 Wnt 途径共定位，并且其被 Wnt 信号诱导，这表明它在黏膜稳态中起作用，但当 Wnt 途径失调时，GPx2 也可能支持肿瘤生长。相比之下，Nrf2 激活剂诱导 GPx2 的产生以及在 GPx2 敲低的细胞中 COX2 的上调表明其抑制炎症，并提示预防炎症介导的致癌作用。GPx2 的两面性作用在炎症相关结直肠癌发生的小鼠模型（AOM/DSS）中得到了证实，在该模型中，GPx2 缺失增加了炎症，进而增加了肿瘤的发展，但肿瘤体积减小。该模型进一步表明，硒（Se）使肿瘤发生减少，而中等 Se 缺乏时 Nrf2 激活剂萝卜硫素具有有害作用，这两种情况均与 GPx2 无关。
