Physiological functions of GPx2 and its role in inflammation-triggered carcinogenesis
Physiological functions of GPx2 and its role in inflammation-triggered carcinogenesis
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DOI：
10.1111/j.1749-6632.2012.06574.x
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发表时间：
2012-01-01
期刊：
影响因子：
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通讯作者：
Kipp, Anna Patricia
中科院分区：
文献类型：
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作者：
Brigelius-Flohe, Regina;Kipp, Anna Patricia
本文综述了哺乳动物谷胱甘肽过氧化物酶（GPxs）的研究进展，重点介绍了胃肠道GPx 2在肿瘤发生中的作用。GPx 2在硒蛋白的等级中排名很高，证实了它的重要性。GPx 2与Wnt通路在肠的隐窝基底中的共定位及其由Wnt信号的诱导指向在粘膜稳态中的作用，但是GPx 2在通过失调的Wnt通路增加时也可能支持肿瘤生长。相反，Nrf 2激活剂对GPx 2的诱导和GPx 2敲低细胞中COX 2的上调揭示了炎症的抑制，并提示预防炎症介导的致癌作用。GPx 2的Janus面作用已在炎症相关结肠癌发生（AOM/DSS）的小鼠模型中得到证实，其中GPx 2缺失增加炎症并因此增加肿瘤发展，但减小肿瘤大小。该模型进一步揭示了硒（Se）引起的肿瘤发展的GPx 2非依赖性降低以及Nrf 2激活剂萝卜硫素在中度硒缺乏中的有害作用。
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.