Case Control Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Dec 15, 2019; 11(12): 1141-1150
Published online Dec 15, 2019. doi: 10.4251/wjgo.v11.i12.1141
Protein expression trends of DNMT1 in gastrointestinal diseases: From benign to precancerous lesions to cancer
Tian-Miao Ma, Li-Ping Sun, Nan-Nan Dong, Ming-Jun Sun, Yuan Yuan
Tian-Miao Ma, Ming-Jun Sun, Department of Gastroenterology, the First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
Li-Ping Sun, Nan-Nan Dong, Yuan Yuan, Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
Author contributions: Yuan Y contributed to study design and manuscript revision; Ma TM contributed to data interpretation, performed the experiments, and drafted the manuscript; Sun LP contributed to experiment instruction, data interpretation, and statistical analysis; Dong NN contributed to sample preparation; and Sun MJ contributed to sample collection and experimental instruction.
Institutional review board statement: The study was approved by the ethics committee of the First Hospital of China Medical University (Shenyang, China).
Informed consent statement: All patients gave informed consent.
Conflict-of-interest statement: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at yuanyuan@cmu.edu.cn
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/
Corresponding author: Yuan Yuan, MD, PhD, Professor, Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, No. 155, Nanjingbei Street, Heping District, Shenyang 110001, Liaoning Province, China. yuanyuan@cmu.edu.cn
Telephone: +86-24-83282153
Received: March 30, 2019
Peer-review started: April 3, 2019
First decision: July 31, 2019
Revised: September 4, 2019
Accepted: September 12, 2019
Article in press: September 13, 2019
Published online: December 15, 2019
ARTICLE HIGHLIGHTS
Research background

In recent years, the incidence of gastrointestinal (GI) cancer in China has increased annually. Early detection and appropriate therapy are considered to be the key to treating GI cancer. Unfortunately, at present, the early detection rates of gastric cancer (GC) and colorectal cancer (CRC) are both less than 10% of all diagnosed cases on average. Previously, we illustrated that the expression of DNMT1 was significantly higher in GC tissues than in non-GC tissues by meta-analysis. Simultaneously, several studies have also revealed that DNMT1 is strongly expressed in GC and CRC, suggesting that DNMT1 could be a potential biomarker in screening of GI cancer. However, the expression of DNMT1 protein in the dynamic variations of GI carcinogenesis, especially in precancerous lesions, is still unclear.

Research motivation

In this study, from the perspective of the evolving process of GI cancer, we measured the expression of DNMT1 protein in different stages of GI diseases (from benign to precancerous to cancerous), investigated its expression characteristics, and further analyzed its clinical application value as a warning biomarker in diagnosis of early GI cancer.

Research objectives

Although we only used patient tissues as our samples to detect the dynamic variation of DNMT1 protein expression in different gastrointestinal diseases, we consider DNMT1 may be used as part of a future serological test to assess the severity of patients with gastrointestinal disorders and to prompt them to complete more tests, which could help to discover the disease as soon as possible and take appropriate treatment next step.

Research methods

A total of 650 patients with different gastrointestinal diseases diagnosed pathologically, who had not received preoperative chemotherapy or radiation, were enrolled in our study. Among them, there were 353 cases of different gastric diseases, including 90 cases of chronic superficial gastritis, 72 cases of atrophic gastritis with intestinal metaplasia (AG/GIM), 54 cases of low-grade intraepithelial neoplasia (GLIN), 66 cases of high-grade intraepithelial neoplasia (GHIN), and 71 cases of early gastric cancer (EGC). In addition, 297 cases of colorectal diseases were also contained in our experiment, including 90 cases of normal intestinal mucosa (NIM), 54 cases of intestinal low-grade intraepithelial neoplasia (ILIN), 71 cases of intestinal high-grade intraepithelial neoplasia (IHIN), and 82 cases of early colorectal cancer (ECRC). Immunohistochemistry (IHC) was used to detect the expression of DNMT1 in these cases. Statistical analysis was performed in any two gastric groups and intestinal groups separately, by rank sum test on the basis of DNMT1 positivity, and P < 0.05 was considered statistically significant.

Research results

In accordance with the results, we could figure out that DNMT1 was hardly expressed in chronic superficial gastritis tissues, but its expression was gradually up-regulated in atrophic gastritis with intestinal metaplasia and low-grade intraepithelial neoplasia tissues, and much higher in high-grade intraepithelial neoplasia and early gastric cancer. This indicated that the expression level of DNMT1 protein increases with the severity of gastric diseases. In different intestinal diseases, the changes in DNMT1 expression were consistent with the dynamic trend in gastric diseases. In the normal intestinal mucosa group, the positive expression rate of DNMT1 was the lowest. And in the intestinal low-grade intraepithelial neoplasia group, there were many weakly or moderately positive cases, and few strongly positive cases. However, in the high-grade intraepithelial neoplasia or early colorectal cancer stage, the positive expression rate of DNMT1 was much higher. In conclusion, the up-regulation of DNMT1 can usually precede the appearance of DNA methylation, which is instructive for estimating the malignancy of precancerous lesions.

Research conclusions

DNMT1 can not only distinguish between normal tissues and cancerous tissues, but also assess the extent of precancerous lesions. With the aggravation of GI mucosal lesions, the expression of DNMT1 is rapidly increasing, which is of great significance for the early diagnosis of GI cancer. DNMT1 is a gene with significantly differential expression in gastrointestinal diseases, and could be used for early diagnosis of GI cancer and guidance of clinical treatment.

Research perspectives

The present study suggested that the expression level of DNMT1 in the gastrointestinal mucosa significantly correlates with disease progression, thus being used as an early warning sign of cancer. In the future, the feasibility of serum DNMT1 expression detection as an early warning sign of gastrointestinal risks can be investigated.