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World J Gastrointest Pathophysiol. Feb 15, 2016; 7(1): 131-137
Published online Feb 15, 2016. doi: 10.4291/wjgp.v7.i1.131
Role of nitric oxide in the pathogenesis of Barrett’s-associated carcinogenesis
Gen Kusaka, Kaname Uno, Katsunori Iijima, Tooru Shimosegawa
Gen Kusaka, Kaname Uno, Katsunori Iijima, Tooru Shimosegawa, Division of Gastroenterology, Tohoku University Hospital, Sendai, Miyagi 981-8574, Japan
Author contributions: All authors contributed to this paper.
Conflict-of-interest statement: None.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Gen Kusaka, MD, PhD, Division of Gastroenterology, Tohoku University Hospital, 1-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi 981-8574, Japan. gkusaka@med.tohoku.ac.jp
Telephone: +81-22-7177171 Fax: +81-22-7177174
Received: June 25, 2015
Peer-review started: June 28, 2015
First decision: August 26, 2015
Revised: October 17, 2015
Accepted: November 10, 2015
Article in press: November 11, 2015
Published online: February 15, 2016
Processing time: 220 Days and 1.9 Hours
Abstract

Barrett’s esophagus (BE), a premalignant condition to Barrett’s adenocarcinoma (BAC), is closely associated with chronic inflammation due to gastro-esophageal reflux. Caudal type homeobox 2 (CDX2), a representative marker of BE, is increased during the metaplastic and neoplastic transformation of BE. Nitric oxide (NO) has been proposed to be a crucial mediator of Barrett’s carcinogenesis. We previously demonstrated that CDX2 might be induced directly under stimulation of large amounts of NO generated around the gastro-esophageal junction (GEJ) by activating epithelial growth factor receptor in a ligand-independent manner. Thus, we reviewed recent developments on the role of NO in Barrett’s carcinogenesis. Notably, recent studies have reported that microbial communities in the distal esophagus are significantly different among groups with a normal esophagus, reflux esophagitis, BE or BAC, despite there being no difference in the bacterial quantity. Considering that microorganism components can be one of the major sources of large amounts of NO, these studies suggest that the bacterial composition in the distal esophagus might play an important role in regulating NO production during the carcinogenic process. Controlling an inflammatory reaction due to gastro-esophageal reflux or bacterial composition around the GEJ might help prevent the progression of Barrett’s carcinogenesis by inhibiting NO production.

Keywords: Barrett’s esophagus; Nitric oxide; Epithelial growth factor receptor; Caudal type homeobox 2; Microbiome

Core tip: Barrett’s carcinogenesis is closely associated with chronic inflammation caused by gastro-esophageal reflux of gastric acid, bile acid and intraluminal microorganisms. Caudal type homeobox 2 (CDX2) is a crucial biomarker of Barrett’s esophagus. We previously demonstrated that a high amount of nitric oxide (NO) at the gastro-esophageal junction (GEJ) might directly induce CDX2 through phosphorylation of epidermal growth factor receptor (EGFR) in a ligand-independent manner. Together with a possible effect of anti-EGFR-targeting drugs in inhibiting Barrett’s adenocarcinoma, future research for controlling NO production around the GEJ might provide a new insight for developing a management strategy of Barrett’s carcinogenesis.