Nakanishi Masako, Perret Christine, Meuillet Emmanuelle J, Rosenberg Daniel W
Center for Molecular Medicine, University of Connecticut Health Center, Farmington, CT, USA, Inserm, U1016, département endocrinologie métabolisme et cancer, Institut Cochin, Paris, France and The University of Arizona Cancer Center, Department of Molecular and Cell Biology, Department of Nutritional Sciences, University of Arizona, Tucson, AZ, USA. Tucson, AZ, USA.
Center for Molecular Medicine, University of Connecticut Health Center, Farmington, CT, USA, Inserm, U1016, département endocrinologie métabolisme et cancer, Institut Cochin, Paris, France and.
Carcinogenesis. 2015 Apr;36(4):478-86. doi: 10.1093/carcin/bgv004. Epub 2015 Jan 29.
Microsomal PGE2 synthase-1 (mPGES-1), the terminal enzyme in the formation of inducible PGE2, represents a potential target for cancer chemoprevention. We have previously shown that genetic abrogation of mPGES-1 significantly suppresses tumorigenesis in two preclinical models of intestinal cancer. In this study, we examined the role of mPGES-1 during colon tumorigenesis in the presence of dextran sulfate sodium (DSS)-induced inflammatory microenvironment. Using Apc (Δ14/+) in which the mPGES-1 gene is either wild-type (D14:WT) or deleted (D14:KO), we report that mPGES-1 deficiency enhances sensitivity to acute mucosal injury. As a result of the increased epithelial damage, protection against adenoma formation is unexpectedly compromised in the D14:KO mice. Examining the DSS-induced acute injury, cryptal structures are formed within inflamed areas of colonic mucosa of both genotypes that display the hallmarks of early neoplasia. When acute epithelial injury is balanced by titration of DSS exposures, however, these small cryptal lesions progress rapidly to adenomas in the D14:WT mice. Given that mPGES-1 is highly expressed within the intestinal stroma under the inflammatory conditions of DSS-induced ulceration, we propose a complex and dual role for inducible PGE2 synthesis within the colonic mucosa. Our data suggest that inducible PGE2 is critical for the maintenance of an intact colonic epithelial barrier, while promoting epithelial regeneration. This function is exploited during neoplastic transformation in Apc (Δ14/+) mice as PGE2 contributes to the growth and expansion of the early initiated cryptal structures. Taken together, inducible PGE2 plays a complex role in inflammation-associated cancers that requires further analysis. Inducible PGE2 production by mPGES-1 is critical for the colonic mucosal homeostasis. This function is exploited in the presence of the neoplastic transformation in Apc (Δ14/+) mice as PGE2 contributes to the growth and expansion of the early cryptal structures.
微粒体前列腺素E2合酶-1（mPGES-1）是诱导型前列腺素E2形成过程中的末端酶，是癌症化学预防的一个潜在靶点。我们之前已经表明，mPGES-1的基因敲除在两种肠道癌临床前模型中显著抑制肿瘤发生。在本研究中，我们研究了在硫酸葡聚糖钠（DSS）诱导的炎症微环境存在下，mPGES-1在结肠肿瘤发生过程中的作用。使用mPGES-1基因要么是野生型（D14:WT）要么被敲除（D14:KO）的Apc（Δ14/+）小鼠，我们报告mPGES-1缺陷增强了对急性粘膜损伤的敏感性。由于上皮损伤增加，D14:KO小鼠中对腺瘤形成的保护意外受损。检查DSS诱导的急性损伤时，两种基因型的结肠粘膜炎症区域内均形成了显示早期肿瘤特征的隐窝结构。然而，当通过滴定DSS暴露来平衡急性上皮损伤时，这些小的隐窝病变在D14:WT小鼠中迅速发展为腺瘤。鉴于mPGES-1在DSS诱导溃疡的炎症条件下在肠道基质中高度表达，我们提出诱导型前列腺素E2在结肠粘膜内的合成具有复杂的双重作用。我们的数据表明，诱导型前列腺素E2对于维持完整的结肠上皮屏障至关重要，同时促进上皮再生。在Apc（Δ14/+）小鼠的肿瘤转化过程中利用了这一功能，因为前列腺素E2有助于早期起始的隐窝结构的生长和扩展。综上所述，诱导型前列腺素E2在炎症相关癌症中发挥复杂作用，需要进一步分析。mPGES-1产生诱导型前列腺素E2对于结肠粘膜稳态至关重要。在Apc（Δ14/+）小鼠存在肿瘤转化的情况下利用了这一功能，因为前列腺素E2有助于早期隐窝结构的生长和扩展。
