Parp-1 deficiency implicated in colon and liver tumorigenesis induced by azoxymethane
Parp-1 deficiency implicated in colon and liver tumorigenesis induced by azoxymethane
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DOI：
10.1111/j.1349-7006.2003.tb01472.x
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发表时间：
2003-06-01
期刊：
影响因子：
5.7
通讯作者：
Masutani, M
中科院分区：
文献类型：
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作者：
Nozaki, T;Fujihara, H;Masutani, M
聚（adp -核糖）聚合酶-1 （Parp-1）被DNA链断裂激活，在维持基因组完整性和细胞死亡控制中起作用。另一方面，Parp-1还参与多种基因的转录调控，缺乏Parp-1与肿瘤易感性之间的关系尚未完全阐明。在本研究中，携带Parp-1外显子1断裂的Parp-1（-/-）小鼠和Parp1（+/+）动物被给予氮氧甲烷（AOM），剂量为10 mg/kg体重，每周1次，持续6周。在第一次致癌物治疗30周后，小鼠被处死。Parp-1（-/-）小鼠结肠腺瘤或腺癌的发生率和每只小鼠结肠肿瘤的平均数量显著高于Parp-1（+/+）小鼠。在43/44的Parp-1（-/-）肿瘤和19/21的Parp-1（+/+）肿瘤中观察到β - catenin积累，在基因型之间无统计学差异。这表明，在Parp-1（-/-）和Parp-1（+/+）小鼠中，大多数肿瘤是通过wnt - β -catenin信号通路的改变而发展的。在AOM主要被激活的肝脏中，与Parp-1（+/+）小鼠相比，Parp-1（-/-）小鼠携带结节的动物发生率和每切片平均结节数显著增加。因此，结果表明Parp-1（-/-）小鼠对aom诱导的结肠和肝脏肿瘤发生的易感性增强，Parp-1可能在结肠和肝脏肿瘤发生中起重要作用。
Poly(ADP-ribose) polymerase-1 (Parp-1) is activated by DNA strand breaks and functions in the maintenance of genomic integrity and cell death control. On the other hand, Parp-1 is also involved in transcriptional regulation of various genes, and the relationship between Parp-1 deficiency and susceptibility to tumorigenesis has not been fully elucidated. In the present study, Parp-1(-/-) mice, harboring exon 1 disruption in Parp-1, and Parp1(+/+) animals were administered azoxymethane (AOM) at a dose of 10 mg/kg body weight once a week for 6 weeks. At 30 weeks after the first carcinogen treatment, mice were sacrificed. The incidence of animals bearing either adenomas or adenocarcinomas in the colon and the average number of colon tumors per mouse were significantly higher in Parp-1(-/-) mice than in Parp-1(+/+) animals. beta-Catenin accumulation was observed in 43/44 of Parp-1(-/-) tumors and 19/21 of the Parp-1(+/+) tumors and was not statistically different between the genotypes. This suggests that most tumors developed through a pathway involving the alteration of Wnt-beta-catenin signaling in both Parp-1(-/-) and Parp-1(+/+) mice. In the liver, where AOM is primarily activated, the incidence of animals bearing nodules and the average number of nodules per section were significantly increased in Parp-1(-/-) mice compared with Parp-1(+/+) mice. Therefore, the results indicate that susceptibility to AOM-induced tumorigenesis in the colon and also in the liver is enhanced in Parp-1(-/-) mice, and Parp-1 could have a substantial role in colon and liver tumorigenesis.