Suh Jung H, Saba Julie D
UCSF Benioff Children's Hospital Oakland, Oakland, USA.
Transl Cancer Res. 2015 Oct 1;4(5):469-483. doi: 10.3978/j.issn.2218-676X.2015.10.06.
Colitis-associated colon cancer (CAC) is a pathological condition defined by the development of colon cancer in patients afflicted by Crohn's disease (CD) or ulcerative colitis (UC), two idiopathic diseases of the gut which together comprise the disease group called inflammatory bowel disease (IBD). When IBD involves the colon, affected patients face an increased risk of developing colon cancer compared to the general population. The phenomenon of CAC represents one of the most convincing forms of evidence linking the processes of inflammation, oxidative stress and carcinogenesis. A greater understanding of the molecular events driving CAC could reveal new strategies to treat IBD and reduce the incidence of CAC. Sphingosine-1-phosphate (S1P) is a bioactive lipid produced through degradation of endogenous and dietary mammalian sphingolipids containing the long chain base sphingosine. S1P signals through a family of five G protein-coupled receptors. In addition, it activates nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3), two transcriptional regulators that serve as master switches in inflammation and carcinogenesis. Through these and other mechanisms, a causal role for S1P in inflammatory conditions including colitis and CAC has been implicated. In contrast to S1P, dietary sphingolipids called sphingadienes derived from plant food sources cannot be converted to S1P and exhibit anti-inflammatory and chemopreventive activities, reducing colitis and CAC in mouse models. In this review, we summarize recent findings implicating S1P signaling and metabolism in the pathogenesis of IBD and CAC. The potential role of oxidative stress in modulating S1P is also discussed. Further, we propose the hypothesis that dietary sphingolipids may promote or prevent CAC depending on their ability to be converted to S1P.
结肠炎相关结肠癌（CAC）是一种病理状态，定义为患有克罗恩病（CD）或溃疡性结肠炎（UC）的患者发生的结肠癌，这两种肠道特发性疾病共同构成了称为炎症性肠病（IBD）的疾病组。当IBD累及结肠时，与普通人群相比，受影响的患者患结肠癌的风险增加。CAC现象是将炎症、氧化应激和致癌过程联系起来的最有说服力的证据形式之一。对驱动CAC的分子事件有更深入的了解可能会揭示治疗IBD和降低CAC发病率的新策略。鞘氨醇-1-磷酸（S1P）是一种生物活性脂质，通过含有长链碱基鞘氨醇的内源性和膳食哺乳动物鞘脂的降解产生。S1P通过一个由五个G蛋白偶联受体组成的家族发出信号。此外，它还激活核因子κB（NF-κB）和信号转导子及转录激活子3（STAT3），这两种转录调节因子在炎症和致癌过程中起主要开关作用。通过这些及其他机制，S1P在包括结肠炎和CAC在内的炎症性疾病中的因果作用已被牵连。与S1P相反，来自植物性食物来源的称为鞘氨二烯的膳食鞘脂不能转化为S1P，并具有抗炎和化学预防活性，可减轻小鼠模型中的结肠炎和CAC。在本综述中，我们总结了最近关于S1P信号传导和代谢在IBD和CAC发病机制中的研究发现。还讨论了氧化应激在调节S1P中的潜在作用。此外，我们提出了一个假说，即膳食鞘脂可能根据其转化为S1P的能力促进或预防CAC。
