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World J Gastroenterol. Jul 28, 2021; 27(28): 4653-4666
Published online Jul 28, 2021. doi: 10.3748/wjg.v27.i28.4653
Genetic variant of cyclooxygenase-2 in gastric cancer: More inflammation and susceptibility
Xuan-Ke Ji, Sailaja Vatsalya Madhurapantula, Gui He, Kun-Yan Wang, Chun-Hua Song, Jian-Ying Zhang, Kai-Juan Wang
Xuan-Ke Ji, Sailaja Vatsalya Madhurapantula, Gui He, Kun-Yan Wang, Chun-Hua Song, Jian-Ying Zhang, Kai-Juan Wang, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
Xuan-Ke Ji, Sailaja Vatsalya Madhurapantula, Gui He, Kun-Yan Wang, Chun-Hua Song, Jian-Ying Zhang, Kai-Juan Wang, Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
Xuan-Ke Ji, Sailaja Vatsalya Madhurapantula, Gui He, Kun-Yan Wang, Chun-Hua Song, Jian-Ying Zhang, Kai-Juan Wang, Key Laboratory of Tumor Epidemiology of Henan Province, Zhengzhou University, Zhengzhou 450001, Henan Province, China
Xuan-Ke Ji, Sailaja Vatsalya Madhurapantula, Gui He, Kun-Yan Wang, Chun-Hua Song, Jian-Ying Zhang, Kai-Juan Wang, State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450001, Henan Province, China
Author contributions: Ji XK, He G, Wang KY, Song CH, Zhang JY, and Wang KJ contributed to conception or design of the study; Ji XK, He G, and Wang KY contributed to acquisition of the data; Ji XK, He G, Wang KY, and Wang KJ contributed to analysis or interpretation of the data; Ji XK contributed to drafting of the manuscript; Madhurapantula SV and Wang KJ contributed to critical revision of the manuscript for important intellectual content.
Supported by National Natural Science Foundation of China, No. 81373097.
Conflict-of-interest statement: The authors declare that they have no conflict of interest to disclose.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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/
Corresponding author: Kai-Juan Wang, PhD, Professor, College of Public Health, Zhengzhou University, No. 100 Kexue Avenue, Zhengzhou 450001, Henan Province, China. kjwang@163.com
Received: January 27, 2021
Peer-review started: January 27, 2021
First decision: March 7, 2021
Revised: March 17, 2021
Accepted: July 2, 2021
Article in press: July 2, 2021
Published online: July 28, 2021
Processing time: 179 Days and 19.5 Hours
Abstract

Gastric cancer accounts for the majority cancer-related deaths worldwide. Although various methods have considerably improved the screening, diagnosis, and treatment of gastric cancer, its incidence is still high in Asia, and the 5-year survival rate of advanced gastric cancer patients is only 10%-20%. Therefore, more effective drugs and better screening strategies are needed for reducing the incidence and mortality of gastric cancer. Cyclooxygenase-2 (COX-2) is considered to be the key inducible enzyme in prostaglandins (PGs) synthesis, which is involved in multiple pathways in the inflammatory response. For example, inflammatory cytokines stimulate innate immune responses via Toll-like receptors and nuclear factor-kappa B to induce COX-2/PGE2 pathway. In these processes, the production of an inflammatory microenvironment promotes the occurrence of gastric cancer. Epidemiological studies have also indicated that non-steroidal anti-inflammatory drugs can reduce the risk of malignant tumors of the digestive system by blocking the effect of COX-2. However, clinical use of COX-2 inhibitors to prevent or treat gastric cancer may be limited because of potential side effects, especially in the cardiovascular system. Given these side effects and low treatment efficacy, new therapeutic approaches and early screening strategies are urgently needed. Some studies have shown that genetic variation in COX-2 also play an important role in carcinogenesis. However, the genetic variation analysis in these studies is incomplete and isolated, pointing out only a few single nucleotide polymorphisms (SNPs) and the risk of gastric cancer, and no comprehensive study covering the whole gene region has been carried out. In addition, copy number variation (CNV) is not mentioned. In this review, we summarize the SNPs in the whole COX-2 gene sequence, including exons, introns, and both the 5’ and 3’ untranslated regions. Results suggest that COX-2 does not increase its expression through the CNV and the SNPs in COX-2 may serve as the potential marker to establish risk stratification in the general population. This review synthesizes emerging insights of COX-2 as a biomarker in multiple studies, summarizes the association between whole COX-2 sequence variation and susceptibility to gastric cancer, and discusses the future prospect of therapeutic intervention, which will be helpful for early screening and further research to find new approaches to gastric cancer treatment.

Keywords: Cyclooxygenase-2; Inflammation; Genetic variant; Gastric cancer; Prostaglandin E2

Core Tip: Cyclooxygenase-2 (COX-2) is considered to be the key inducible enzyme in prostaglandins synthesis, and non-steroidal anti-inflammatory drugs can reduce the risk of malignant tumors of the digestive system by blocking the effect of COX-2. However, COX-2 inhibitors to prevent or treat gastric cancer may be limited because of their cardiovascular side effects. This review will be helpful for early screening and further research to find new approaches to gastric cancer treatment by summarizing the association between whole COX-2 sequence variation and susceptibility to gastric cancer and synthesizing the new progress in understanding the role of COX-2 in gastric carcinogenesis.