Helicobacter pylori induces caudal-type homeobox protein 2 and cyclooxygenase 2 expression by modulating microRNAs in esophageal epithelial cells.

Dysregulation of microRNAs (miRNAs) has been linked to virulence factors of Helicobacter pylori. The role of H. pylori in esophageal disease has not been clearly defined. We previously reported that H. pylori esophageal colonization promotes the incidence of Barrett's esophagus and esophageal adenocarcinoma in vivo. Here, we studied the direct effects of H. pylori on the transformation of esophageal epithelial cells, with particular focus on whether H. pylori exerts its effects by modulating miRNAs and their downstream target genes. The normal human esophageal cell line HET-1A was chronically exposed to H. pylori extract and/or acidified deoxycholic acid for up to 36 weeks. The miRNA profiles of the esophageal epithelial cells associated with H. pylori infection were determined by microarray analysis. We found that chronic H. pylori exposure promoted acidified deoxycholic acid-induced morphological changes in HET-1A cells, along with aberrant overexpression of intestinal metaplasia markers and tumorigenic factors, including caudal-type homeobox protein 2 (CDX2), mucin 2, and cyclooxygenase 2 (COX2). Helicobacter pylori modified the miRNA profiles of esophageal epithelial cells, particularly aberrant silencing of miR-212-3p and miR-361-3p. Moreover, in biopsies from Barrett's esophagus patients, esophageal H. pylori colonization was associated with a significant decrease in miR-212-3p and miR-361-3p expression. Furthermore, we identified COX2 as a target of miR-212-3p, and CDX2 as a target of miR-361-3p. Helicobacter pylori infection of esophageal epithelial cells was associated with miRNA-mediated upregulation of oncoprotein CDX2 and COX2. Our observations provide new evidence about the molecular mechanisms underlying the association between H. pylori infection and esophageal carcinogenesis.

Macrophage targeting contributes to the inhibitory effects of embelin on colitis-associated cancer.

Macrophages are a major component of inflammatory and tumor microenvironment. We previously reported that embelin suppresses colitis-associated tumorigenesis. Here, the role of macrophage targeting in the anti-inflammatory and anti-tumor properties of embelin was investigated. By using colitis-associated cancer (CAC) model, we demonstrated that embelin significantly depleted colon macrophages by blocking their recruitment. Moreover, embelin attenuated M2-like polarization of macrophages within the tumor microenvironment and eliminated their tumor-promoting functions during the development of CAC. Embelin potently inhibited NF-κB signaling in macrophages and decreased the production of key pro-inflammatory cytokines and tumorigenic factors involved in CAC, such as TNFα, IL-6 and COX-2. In addition, embelin directly reduced the polarization of M2 macrophages in vitro even in the presence of Th2 cytokines. These results suggested that targeting macrophages is, at least in part, responsible for the anti-tumor activity of embelin in CAC. Our observations strengthen the rationale for future validation of embelin in the prevention and treatment of CAC.

Expression and localization of c-Fos and NOS in the central nerve system following esophageal acid stimulation in rats.

AIM: To determine the distribution of neurons expressing c-Fos and nitric oxide synthase (NOS) in the central nerve system (CNS) following esophageal acid exposure, and to investigate the relationship between c-Fos and NOS. METHODS: Twelve Wistar rats were randomly divided into two equal groups. Hydrochloric acid with pepsin was perfused in the lower part of the esophagus for 60 min. As a control, normal saline was used. Thirty minutes after the perfusion, the rats were killed and brains were removed and processed for c-Fos immunohistochemistry and NADPH-d histochemistry. Blood pressure (BP), heart rate (HR), and respiratory rate (RR) during the experimental procedures were recorded every 10 min. RESULTS: There were no significant differences in BP, HR and RR between the two groups. c-Fos immunoreactivity was significantly increased in rats receiving acid plus pepsin perfusion in amygdala (AM), paraventricular nucleus (PVN), parabrachial nucleus (PBN), nucleus tractus solitarius and dorsal motor nucleus of vagus (NTS/DMV), nucleus ambiguous (NA), reticular nucleus of medulla (RNM) and area postrema (AP). NOS reactivity in this group was significantly increased in PVN, PBN, NTS/DMV, RNM and AP. c-Fos and NOS had significant correlation between PVN, PBN, NTS/DMV, RNM and AP. CONCLUSION: Acid plus pepsin perfusion of the esophagus results in neural activation in areas of CNS, and NO is likely one of the neurotransmitters in some of these areas.