State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, China; Department of Pediatric Surgery, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China.
State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China; Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, China; Wuxi Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Wuxi, 214002, China.
Free Radic Biol Med. 2021 Feb 20;164:390-398. doi: 10.1016/j.freeradbiomed.2020.12.456. Epub 2021 Jan 16.
The etiology and pathogenesis of Hirschsprung's disease (HSCR) remain largely unknown. We examined colon tissues from three independent populations with a combined analysis of metabolomics, transcriptomics and proteomics to understand HSCR pathogenesis, according to which mouse model was used to examine prostaglandin E2 (PGE2) induced clinical presentation of HSCR. SH-SY5Y and SK-N-BE(2) cell lines were studied for PGE2 inhibited cell migration through EP2. Our integrated multiple 'omics'-analysis suggests that the levels of PGE2, the expression of the gene encoding PGE2 receptor (EP2), and PGE2 synthesis enzyme genes (PTGS1 and PTGES) increased in HSCR colon tissues, together with a decreased synthesis of PGE2-related byproducts. In vivo, the pregnant mice treated with PGE2 gave birth to offspring with the decrease of ganglion cells in their colon and gut function. In in vitro study, when EP2 was blocked, the PGE2-inhibited cell migration was recovered. Our study identified a novel pathway highlighting the link between expression of PTGS1 and PTGES, levels of PGE2, expression of PTGER2, and neural crest cell migration in HSCR, providing a novel strategy for future diagnosis and prevention of HSCR.
先天性巨结肠症（HSCR）的病因和发病机制在很大程度上仍不清楚。我们通过代谢组学、转录组学和蛋白质组学的综合分析，研究了来自三个独立人群的结肠组织，以了解 HSCR 的发病机制，并根据该分析结果使用小鼠模型来研究前列腺素 E2（PGE2）诱导的 HSCR 临床表型。我们还研究了 SH-SY5Y 和 SK-N-BE(2)细胞系中 PGE2 通过 EP2 抑制细胞迁移的情况。我们的综合多组学分析表明，HSCR 结肠组织中 PGE2 的水平、编码 PGE2 受体（EP2）的基因表达以及 PGE2 合成酶基因（PTGS1 和 PTGES）增加，同时 PGE2 相关副产物的合成减少。在体内，用 PGE2 处理怀孕的小鼠，其后代的结肠和肠道功能中的神经节细胞减少。在体外研究中，当阻断 EP2 时，PGE2 抑制的细胞迁移得到恢复。我们的研究确定了一条新途径，强调了 PTGS1 和 PTGES 的表达、PGE2 的水平、PTGER2 的表达和神经嵴细胞迁移之间的联系，为 HSCR 的未来诊断和预防提供了新策略。
