Activation of the peroxisome proliferator-activated receptor γ promotes the development of colon tumors in C57BL/6J-APCMin/+ mice
Activation of the peroxisome proliferator-activated receptor γ promotes the development of colon tumors in C57BL/6J-APCMin/+ mice
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DOI：
10.1038/2036
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发表时间：
1998-09-01
期刊：
影响因子：
82.9
通讯作者：
Auwerx, J
中科院分区：
文献类型：
--
作者：
Lefebvre, AM;Chen, IH;Auwerx, J
结肠直肠癌是最常见的癌症之一，其发展受到前列腺素和脂肪酸的影响。前列腺素的产生减少，在环氧合酶2基因突变的小鼠或用环氧合酶抑制剂治疗的动物和人类中观察到，预防或减弱结肠癌的发展（2-4）。从动物来源的脂肪酸的摄入量和结肠癌之间也有很强的相关性（5，6）。因此，过氧化物酶体增殖物激活受体γ（过氧化物酶体增殖物激活受体γ;参考文献7），一种在结肠中高度表达的胰高血糖素和脂肪酸的下游转录介质（8，9），可能参与了这一过程。在C57 BL/6 J-APC（Min）/+小鼠（一种易患肠肿瘤的动物模型）中，两种不同的合成激动剂激活PPAR γ可增加结肠肿瘤的发生频率和大小。肿瘤发生率仅在结肠中增加，而在小肠中没有变化，这与PPAR γ的结肠限制性表达一致。在C57 BL/6 J-APC（Min）/+小鼠的结肠和HT-29结肠癌细胞中，用PPAR γ激动剂处理增加了β-连环蛋白水平。Wnt/wingless/APC途径的遗传异常，增强β-连环蛋白-T细胞因子/淋巴增强因子1转录复合物的转录活性，通常是结肠肿瘤发生的基础。我们的数据表明，PPARgamma激活改变了C57 BL/6 J-APC（Min）/+小鼠结肠肿瘤的发展。
The development of colorectal cancer, one of the most frequent cancers, is influenced by prostaglandins and fatty acids' Decreased prostaglandin production, seen in mice with mutations in the cyclooxygenase 2 gene or in animals and humans treated with cyclooxygenase inhibitors, prevents or attenuates colon cancer development(2-4). There is also a strong correlation between the intake of fatty acids from animal origin and colon cancer(5,6). Therefore, the peroxisome proliferator-activated receptor gamma (PPAR gamma; ref. 7), a downstream transcriptional mediator for prostaglandins and fatty acids which is highly expressed in the colon(8,9), may be involved in this process. Activation of PPAR gamma by two different synthetic agonists increased the frequency and size of colon tumors in C57BL/6J-APC(Min)/+ mice, an animal model susceptible to intestinal neoplasia. Tumor frequency was only increased in the colon, and did not change in the small intestine, coinciding with the colon-restricted expression of PPAR gamma. Treatment with PPAR gamma agonists increased beta-catenin levels both in the colon of C57BL/6J-APC(Min)/+ mice and in HT-29 colon carcinoma cells. Genetic abnormalities in the Wnt/wingless/APC pathway, which enhance the transcriptional activity of the beta-catenin-T-cell factor/lymphoid enhancer factor 1 transcription complex, often underly the development of colon tumors. Our data indicate that PPAR gamma activation modifies the development of colon tumors in C57BL/6J-APC(Min)/+ mice.