Lack of inducible nitric oxide synthase promotes intestinal tumorigenesis in the ApcMin/+ mouse
Lack of inducible nitric oxide synthase promotes intestinal tumorigenesis in the ApcMin/+ mouse
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DOI：
10.1053/gast.2001.27994
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发表时间：
2001-10-01
期刊：
影响因子：
29.4
通讯作者：
Coletta, PL
中科院分区：
文献类型：
--
作者：
Scott, DJ;Hull, MA;Coletta, PL
背景与目的：诱导型一氧化氮合酶（Nos 2或iNOS）在肠道肿瘤发生中的作用尚不清楚。还存在关于Nos 2调节环加氧酶2（考克斯-2）的表达和/或活性的能力的证实数据，所述环加氧酶2促进肠肿瘤发生。因此，我们在家族性腺瘤性息肉病的Apc（Min/+）小鼠模型中确定了无效Nos 2基因型对肠道肿瘤发生和考克斯-2表达/活性的影响。方法：通过C57 BL/6-Apc（Min/+）和C57 BL/6-Nos 2（tm 1 Lau）小鼠之间的连续杂交产生Apc（Min/+）Nos 2（-/-）小鼠。比较年龄匹配的Apc（Min/+）Nos 2（+/+）和Apc（Min/+）Nos 2（-/-）小鼠的腺瘤特征。测定Apc（Min/+）Nos 2（+/+）小鼠小肠Nos 2信使RNA（mRNA）的表达水平和细胞定位。在体外肠组织和骨髓源性巨噬细胞中测量了考克斯-2的表达和活性。结果：Apc（Min/+）Nos 2（-/-）小鼠的肠腺瘤发生率显著高于Apc（Min/+）Nos 2（+/+）同窝小鼠。与组织学正常的Apc（Min/+）Nos 2（+/+）肠相比，腺瘤中上皮细胞Nos 2 mRNA表达降低。在Apc（Min/+）Nos 2（+/+）和Apc（Min/+）Nos 2（-/-）动物的肠或骨髓来源的巨噬细胞中，考克斯-2表达或活性没有显著差异。结论：Nos 2在Apc（Min/+）小鼠家族性腺瘤性息肉病模型中起重要作用。Nos 2不调节Apc（Min/+）小鼠中的考克斯-2表达或活性。
Background & Aims: The role of the inducible isoform of nitric oxide synthase (Nos2 or iNOS) in intestinal tumorigenesis is unclear. Conflicting data also exist regarding the ability of Nos2 to modulate expression and/or activity of cyclooxygenase 2 (Cox-2), which promotes intestinal tumorigenesis. Therefore, we determined the effect of a null Nos2 genotype on intestinal tumorigenesis and Cox-2 expression/activity in the Apc(Min/+) mouse model of familial adenomatous polyposis. Methods; Apc(Min/+)Nos2(-/-) mice were generated by successive crosses between C57BL/6-Apc(Min/+) and C57BL/6-Nos2(tm1Lau) mice. Adenoma characteristics of age-matched Apc(Min/+)Nos2(+/+) and Apc(Min/+)Nos2(-/-) mice were compared. The level and cellular localization of Nos2 messenger RNA (mRNA) expression in Apc(Min/+)Nos2(+/+) mouse intestine was determined. Cox-2 expression and activity were measured in both intestinal tissue and bone marrow-derived macrophages in vitro. Results: Apc(Min/+)Nos2(-/-) mice developed significantly more intestinal adenomas than Apc(Min/+)Nos2(+/+) littermates. Epithelial cell Nos2 mRNA expression was decreased in adenomas compared with histologically normal Apc(Min/+)Nos2(+/+) intestine. There was no significant difference in Cox-2 expression or activity in either intestine or bone marrow-derived macrophages from Apc(Min/+)Nos2(+/+) and Apc(Min/+)Nos2(-/-) animals. Conclusions: Nos2 plays an antineoplastic role in the Apc(Min/+) mouse model of familial adenomatous polyposis. Nos2 does not modulate Cox-2 expression or activity in the Apc(Min/+) mouse.