Short chain fatty acid butyrate uptake reduces expressions of prostanoid EP4 receptors and their mediation of cyclooxygenase-2 induction in HCA-7 human colon cancer cells
Short chain fatty acid butyrate uptake reduces expressions of prostanoid EP4 receptors and their mediation of cyclooxygenase-2 induction in HCA-7 human colon cancer cells
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DOI：
10.1016/j.ejphar.2019.04.014
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发表时间：
2019-06-15
影响因子：
5
通讯作者：
Fujino, Hiromichi
中科院分区：
文献类型：
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作者：
Kurata, Naoki;Tokashiki, Natsumi;Fujino, Hiromichi
微生物群通过人类结肠中膳食纤维的发酵产生短链脂肪酸（SCFA），众所周知，短链脂肪酸可以维持肠道稳态。在 SCFA 中，丁酸盐被认为是对结直肠上皮细胞生长和分化最生理有效的 SCFA。在这里，我们发现，在人结肠癌 HCA-7 细胞中，E 型前列腺素 4 (EP4) 受体表达水平受不同浓度的丁酸盐调节，但不受其他 SCFA 调节，通过钠偶联单羧酸转运蛋白 1 (SMCT-1) 介导的摄取，然后激活组蛋白乙酰转移酶：cAMP 反应元件结合蛋白结合蛋白/p300。特别令人感兴趣的是，已知前列腺素EP4受体在正常结直肠隐窝上皮细胞中表达，并通过保护粘膜完整性来维持肠道稳态，同时它们也参与癌发生的早期阶段。因此，丁酸和前列腺素EP4受体表达之间的联系都是维持体内平衡的重要因素。根据二氧化硅分析，与健康的相应组织相比，几乎一半的结直肠癌组织失去了 SMCT-1 mRNA 的表达。因此，随着体内平衡系统的崩溃，例如结直肠组织中丁酸盐浓度的降低，或丁酸盐摄取的减少，就有可能发展为早期结直肠癌；正常细胞向癌性表型的转化可能是由于前列腺素类EP4受体过度表达，随后过度诱导环氧合酶-2，这是由结直肠上皮细胞内/周围的丁酸盐和/或其摄取量减少引起的。
Microbiota produce short chain fatty acids (SCFAs), which are known to maintain gut homeostasis, by the fermentation of dietary fiber in the human colon. Among SCFAs, butyrate has been considered as the most physiologically effective SCFA in colorectal epithelial cells for growth and differentiation. Here we show that the E-type prostanoid 4 (EP4) receptor expression level is regulated by different concentrations of butyrate, but not by other SCFAs, in human colon cancer HCA-7 cells, through sodium-coupled monocarboxylate transporter-1 (SMCT-1)-mediated uptake followed by the activation of histone acetyltransferase: cAMP response element binding protein-binding protein/p300. Of particular interest, the prostanoid EP4 receptors are known to be expressed in normal colorectal crypt epithelial cells and maintain intestinal homeostasis by preserving mucosal integrity, while they are also known to be involved in the early stage of carcinogenesis. Thus, the links between butyrate and the expression of prostanoid EP4 receptors are both important factors for maintaining homeostasis. Based on in silica analysis, almost half of colorectal cancer tissues have lost the expression of SMCT-1 mRNA when compared with healthy corresponding tissues. Therefore, with the collapse of homeostasis systems such as a decrease in the concentration of butyrate in colorectal tissues, or reduced butyrate uptake, there is a possibility of early stage colorectal cancer development; the transformation of normal cells to the cancerous phenotype may be due to the overexpression of prostanoid EP4 receptors followed by excessive cyclooxygenase-2 induction, which are caused by a reduced amount of butyrate and/or its uptake, in/around colorectal epithelial cells.