Scott D J, Hull M A, Cartwright E J, Lam W K, Tisbury A, Poulsom R, Markham A F, Bonifer C, Coletta P L
Molecular Medicine Unit, University of Leeds, St James's University Hospital, Leeds, England, UK.
Gastroenterology. 2001 Oct;121(4):889-99. doi: 10.1053/gast.2001.27994.
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.
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.
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.
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.
一氧化氮合酶（Nos2或诱导型一氧化氮合酶）的诱导异构体在肠道肿瘤发生中的作用尚不清楚。关于Nos2调节促进肠道肿瘤发生的环氧合酶2（Cox-2）表达和/或活性的能力，也存在相互矛盾的数据。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Nos2基因敲除对肠道肿瘤发生及Cox-2表达/活性的影响。
通过C57BL/6-Apc(Min/+)和C57BL/6-Nos2(tm1Lau)小鼠连续杂交，培育出Apc(Min/+)Nos2(-/-)小鼠。比较年龄匹配的Apc(Min/+)Nos2(+/+)和Apc(Min/+)Nos2(-/-)小鼠的腺瘤特征。测定Apc(Min/+)Nos2(+/+)小鼠肠道中Nos2信使核糖核酸（mRNA）表达的水平及细胞定位。体外测量肠道组织和骨髓来源巨噬细胞中的Cox-2表达和活性。
Apc(Min/+)Nos2(-/-)小鼠发生的肠道腺瘤明显多于同窝的Apc(Min/+)Nos2(+/+)小鼠。与组织学正常的Apc(Min/+)Nos2(+/+)肠道相比，腺瘤中上皮细胞Nos2 mRNA表达降低。Apc(Min/+)Nos2(+/+)和Apc(Min/+)Nos2(-/-)动物的肠道或骨髓来源巨噬细胞中，Cox-2表达或活性无显著差异。
在家族性腺瘤性息肉病的Apc(Min/+)小鼠模型中，Nos2发挥抗肿瘤作用。在Apc(Min/+)小鼠中，Nos2不调节Cox-2的表达或活性。
