Endogenous conversion of-6 to-3 polyunsaturated fatty acids in fat-1 mice attenuated intestinal polyposis by either inhibiting COX-2/-catenin signaling or activating 15-PGDH/IL-18
Endogenous conversion of-6 to-3 polyunsaturated fatty acids in fat-1 mice attenuated intestinal polyposis by either inhibiting COX-2/-catenin signaling or activating 15-PGDH/IL-18
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DOI：
10.1002/ijc.29956
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发表时间：
2016-05-01
影响因子：
6.4
通讯作者：
Hahm, Ki Baik
中科院分区：
文献类型：
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作者：
Han, Young-Min;Park, Jong-Min;Hahm, Ki Baik
Omega-3多不饱和脂肪酸（-3PUFA）在各种临床前癌症模型中具有抑制作用，但它们在肠息肉病中的作用从未被研究过。由于已经尝试使用营养干预来对抗结肠癌的发展，在本研究中，我们评估了-3 PUFA对Apc（Min/+）小鼠模型中肠息肉病的影响。实验组包括野生型C56 BL/6小鼠、Apc（Min/+）小鼠、表达n-3去饱和酶以使-3 PUFA合成的fat-1转基因小鼠和Apc（Min/+）x fat-1双转基因小鼠;所有小鼠均为20周龄。收集小肠进行大体和病理评价，包括评估息肉数量和大小，然后进行免疫组织化学染色和Western印迹。给C57 BL 6小鼠灌胃不同浓度的-3 PUFA后，用GC/MS/MS分析小肠组织中PUFA的含量，并与fat-1小鼠比较。结果，-3 PUFAs显著减弱Apc突变诱导的肠息肉病，同时显著抑制Wnt/β-连环蛋白信号传导、考克斯-2和PGE（2），但诱导显著水平的15-PGDH。此外，在Apc（Min/+）x fat-1小鼠中观察到炎性小体相关底物（如IL-1和IL-18）的显著诱导以及caspase-1的活化。给予至少3 g/60 kg-3 PUFA相当于fat-1小鼠中产生的-3 PUFA，并导致IL-1、半胱天冬酶-3和IL-18的表达显著增加，如在Apc（Min/+）x fat-1小鼠中所见。我们的结论是，-3 PUFAs可以通过抑制Wnt/-catenin信号传导，但增加15-PGDH和IL-18的水平来预防肠息肉的形成。ω-3多不饱和脂肪酸（-3 PUFA）的癌症预防潜力具有极大的临床意义，特别是在受饮食强烈影响的结直肠癌的情况下。然而，-3 PUFA抑制息肉形成的机制基础在很大程度上仍然未知。在该研究中，-3 PUFA对体内肠息肉病的抑制作用与抑制考克斯-2和Wnt/β-连环蛋白信号传导以及诱导15-PGDH和IL-18有关。研究结果表明，-3 PUFA摄入量是临床相关的，特别是在息肉切除术后和家族性腺瘤性息肉病的监测中。
Omega-3 polyunsaturated fatty acids (-3PUFAs) have inhibitory effects in various preclinical cancer models, but their effects in intestinal polyposis have never been examined. As attempts have been made to use nutritional intervention to counteract colon cancer development, in this study we evaluated the effects of -3 PUFAs on intestinal polyposis in the Apc(Min/+) mouse model. The experimental groups included wild-type C56BL/6 mice, Apc(Min/+) mice, fat-1 transgenic mice expressing an n-3 desaturase to enable -3 PUFA synthesis, and Apc(Min/+) x fat-1 double-transgenic mice; all mice were 20 weeks of age. Small intestines were collected for gross and pathologic evaluation, including assessment of polyp number and size, followed by immunohistochemical staining and Western blotting. After administration of various concentrations of -3 PUFAs, PUFA levels were measured in small intestine tissue by GC/MS/MS analysis to compare with PUFA synthesis of between C57BL6 and fat-1mice. As a result, -3 PUFAs significantly attenuated Apc mutation-induced intestinal polyposis accompanied with significant inhibition of Wnt/-catenin signaling, COX-2 and PGE(2,) but induced significant levels of 15-PGDH. In addition, significant induction of the inflammasome-related substrates as IL-1 and IL-18 and activation of caspase-1 was observed in Apc(Min/+) x fat-1 mice. Administration of at least 3 g/60 kg -3 PUFAs was equivalent to -3 PUFAs produced in fat-1 mice and resulted in significant increase in the expression of IL-1, caspase-3 and IL-18, as seen in Apc(Min/+) x fat-1 mice. We conclude that -3PUFAs can prevent intestinal polyp formation by inhibition of Wnt/-catenin signaling, but increased levels of 15-PGDH and IL-18.What's new? The cancer-preventive potential for omega-3 polyunsaturated fatty acids (-3 PUFAs) is of great clinical interest, especially in the case of colorectal cancer, which is strongly influenced by diet. However, the mechanistic basis by which -3 PUFAs suppress polyp formation remains largely unknown. In this study, the suppressive effects of -3 PUFAs on intestinal polyposis in vivo were linked to the inhibition of COX-2 and Wnt/-catenin signaling and to the induction of 15-PGDH and IL-18. The findings suggest that -3 PUFA intake is clinically relevant, particularly following polypectomy and in the surveillance of familial adenomatous polyposis.