Notch Signaling Pathway Is Inhibited in the Development of Barrett’s Esophagus: An In Vivo and In Vitro Study

Abstract

Objective To explore the role of Notch signaling in the development of Barrett's esophagus. Methods Patients with esophagectomy and gastric interposition were recruited as a human model of gastroesophageal reflux disease. The expressions of Notch signaling genes in normal esophagus from surgical specimen and columnar metaplasia in the esophageal remnant after esophagectomy were evaluated by real time quantitative Polymerase Chain Reaction (RT-qPCR) and immunohistochemistry (IHC). For in vitro experiments, Het-1A cells were treated with hydrochloric acid, deoxycholic acid, mixture of hydrochloric acid and deoxycholic acid, or Notch1-siRNA, and expressions of Notch1, Hes1, MUC2, and K13 were evaluated via RT-qPCR and western blot. Results Samples were obtained from 36 patients with columnar metaplasia in the esophageal remnant. Both IHC and RT-qPCR indicated that Notch1 and Hes1 expressions were significantly higher in normal esophagus than that in metaplasia. Hydrochloric acid and deoxycholic acid suppressed Notch1, Hes1, and K13 expressions, in concert with increasing MUC2 expressions. Notch inhibition by Notch1-siRNA contributed to the downregulation of Notch1, Hes1, and K13 expressions, whereas MUC2 expression was enhanced. Conclusions Both hydrochloric acid and deoxycholic acid could suppress Notch signaling pathway in esophageal epithelial cells, and inhibited Notch signaling has important functions in the development of Barrett's esophagus.

The role of bile acids in the development of Barrett’s Oesophagus and Oesophageal Adenocarcinoma: a systematic review

“…In one BO study, DCA increased phospho-38 (67). DCA suppressed Notch 1 activity in BO (62), whereas TDCA exposure significantly increased Notch 4 in BO (73). UDCA did not change Ki67 levels in BO (60).…”

“…Three studies were carried out in human tissue (51,60,61), two on human cell-lines (48,63) and one examined the effects of BAs on both human tissue and cell-lines (62). Two of these studies focused on non-malignant oesophageal cells (61,62) while four focused on BO (48,51,60,63). Three studies examined the effects of DCA on DNA damage (62,63) whereas the effects of UDCA, TDCA, TCA + GCA mixture, UDCA and DCA (separate experiments) were examined in one study each (48,51,60,61).…”

“…Four studies were carried out on non-malignant oesophageal cells (65,66,70,71), while others focused on BO (n=5) (32,51,62,67,69) and OAC (n=1) (68). Most of the studies investigated the effects of DCA alone (n=5) (32,62,67,68,70).…”

“…DCA also: induced expression of COX-2 and PGE2 (BO) (67); increased MUC2 expression (BO) (62); decreased Notch 1-4 (BO) (32); and activated COX-2 and IκBα expression (OAC) (68). Peng et al demonstrated that, in BO, DCA activated the inflammatory markers, p-H2AX, phospho-p65 and NF-κB (51); by contrast, UDCA upregulated levels of the anti-inflammatory GPX1 and catalase enzymes in BO (51).…”

Bile acids inhibit Notch-1 expression in the development of Barrett’s esophagus

“…Several signaling pathways, including Notch, Wnt, and bone morphogenetic protein (BMP) have been shown to play a fundamental role in both embryonic intestinal development and adult intestinal homeostasis (14)(15)(16) . The Notch signaling pathway is a fundamental molecular signaling system that controls cell fate and differentiation of secretory goblet cells (17,18) . Loss of Notch signaling is essential for the differentiation of goblet cell lineage in the small intestine.…”