Nonsteroidal anti-inflammatory drug-activated gene-1 over expression in transgenic mice suppresses intestinal neoplasia
Nonsteroidal anti-inflammatory drug-activated gene-1 over expression in transgenic mice suppresses intestinal neoplasia
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DOI：
10.1053/j.gastro.2006.09.015
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发表时间：
2006-11-01
期刊：
影响因子：
29.4
通讯作者：
Eling, Thomas E.
中科院分区：
文献类型：
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作者：
Baek, Seung Joon;Okazaki, Ryuji;Eling, Thomas E.
背景和目的：非甾体抗炎药物激活基因（NAG-1）在体外被鉴定为一种促凋亡、抗肿瘤发生蛋白，由包括环氧合酶抑制剂在内的许多抗肿瘤发生和化学预防药物诱导。然而，其体内抗肿瘤活性尚未阐明。方法：产生了在鸡β-肌动蛋白启动子（CAG）控制下普遍过表达人NAG-1的转基因小鼠。对 NAG-1 转基因小鼠 (NAG-(Tg+)) 进行表征，然后用两种结直肠癌模型评估其抗肿瘤活性：氧化偶氮甲烷化学诱导和 Apc(Min+) 突变遗传诱导。结果：NAG-(Tg+) 除了体重减轻外没有表现出明显的表型，特别是在男性中。为了检查NAG-1表达是否会抑制肠道肿瘤发生，用结直肠致癌物氧化偶氮处理NAG(-Tg+)小鼠，与非转基因同窝小鼠相比，NAG-(Tg+)小鼠产生的异常隐窝病灶减少了50%，并且没有肿瘤。这一结果表明，这种人类蛋白质的体内表达可以抑制化学诱导的结肠癌发生。 NAG-(Tg+)小鼠也与Apc(Min+)小鼠杂交以确定转基因对肠息肉形成的影响。与非转基因 Apc(Min+) 同窝小鼠相比，Apc(Min+) 突变杂合的 NAG-(Tg+) 小鼠息肉负荷显着降低 (60%)。结论：我们的结果支持NAG-1作为体内肠腺瘤生长的重要调节因子，并表明NAG-1可能充当抑癌基因。
Background & Aims: The nonsteroidal anti-inflammatory drug-activated gene (NAG-1) was identified as a proapoptotic, antitumorigenic protein in vitro, induced by many antitumorigenic and chemopreventive drugs including cyclooxygenase inhibitors. However, its antitumorigenic activity has not been elucidated in vivo. Methods: Transgenic mice were generated that ubiquitously overexpress human NAG-1 under the control of a chicken beta-actin promoter (CAG). The NAG-1 transgenic mice (NAG-(Tg+)) were characterized , and then the antitumorigenic activity was evaluated with 2 colorectal carcinogenesis models: chemical induction with azoxymethane and genetic induction using the Apc(Min+) mutation. Results: NAG-(Tg+) showed no apparent phenotype other than a reduction in body weight, particularly in males. To examine whether NAG-1 expression would suppress intestinal tumorigenesis, the NAG(-Tg+) mice were treated with the colorectal carcinogen azoxymethane, NAG-(Tg+) mice developed 50% fewer aberrant crypt foci and no tumors, in comparison with nontransgenic littermates. This result demonstrates that expression of this human protein in vivo can suppress chemically induced carcinogenesis in the colon. The NAG-(Tg+) mice were also crossed with Apc(Min+) mice to determine the effect of the transgene on intestinal polyp formation. NAG-(Tg+) mice heterozygous for the Apc(Min+) mutation had a significantly reduced polyp load (60%) compared with nontransgenic Apc(Min+) littermates. Conclusions: Our results support NAG-1 as an important regulator of intestinal adenoma growth in vivoand suggest that NAG-1 may act as a tumor suppressor gene.