Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Jul 15, 2024; 16(7): 3211-3229
Published online Jul 15, 2024. doi: 10.4251/wjgo.v16.i7.3211
Weiwei Decoction alleviates gastric intestinal metaplasia through the olfactomedin 4/nucleotide-binding oligomerization domain 1/caudal-type homeobox gene 2 signaling pathway
Di-Shu Zhou, Wei-Jian Zhang, Shu-Ya Song, Xin-Xin Hong, Wei-Qin Yang, Juan-Juan Li, Jian-Qu Xu, Jian-Yuan Kang, Tian-Tian Cai, Yi-Fei Xu, Shao-Ju Guo, Hua-Feng Pan, Hai-Wen Li
Di-Shu Zhou, Wei-Jian Zhang, Xin-Xin Hong, Juan-Juan Li, Jian-Qu Xu, Jian-Yuan Kang, Tian-Tian Cai, Yi-Fei Xu, Shao-Ju Guo, Hai-Wen Li, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
Di-Shu Zhou, Wei-Jian Zhang, Shu-Ya Song, Hua-Feng Pan, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong Province, China
Wei-Qin Yang, Department of Chinese Medicine, The Eight Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518033, Guangdong Province, China
Author contributions: Zhou DS, Zhang WJ, and Song SY wrote the original draft, designed and conducted the experiment; Hong XX, Yang WQ, and Li JJ edited the manuscript and analyzed the data; Xu JQ, Kang JY, Cai TT, and Xu YF edited the manuscript; Guo SJ and Pan HF reviewed the manuscript and administered the project; Li HW reviewed the manuscript, designed the research study, and administered the project; and all authors have read and approved the final manuscript.
Supported by National Natural Science Foundation of China, No. 82104747 and No. 82305133; Basic and Applied Basic Research Foundation of Guangdong Province, China, No. 2020A1515110947; General Project of Shenzhen Science and Technology Innovation Commission, No. JCYJ20230807094659030, No. JCYJ20230807094805012, No. JCYJ20210324111602007, and No. JCYJ20220531091815034; and the Scientific Research Project of Guangdong Provincial Bureau of Traditional Chinese Medicine, No. 20221349.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board at Guangzhou University of Chinese Medicine (No. 20211105008) and Shenzhen Traditional Chinese Medicine Hospital (No. K2022-011-02).
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Center of Science and Technology Innovation, Guangzhou University of Chinese Medicine (No. 20211105008).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
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: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Hai-Wen Li, MD, Attending Doctor, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, No. 1 Fuhua Road, Futian District, Shenzhen 518033, Guangdong Province, China. 370062941@qq.com
Received: February 15, 2024
Revised: April 25, 2024
Accepted: May 11, 2024
Published online: July 15, 2024
Processing time: 148 Days and 11 Hours
Abstract
BACKGROUND

Gastric intestinal metaplasia (IM) is a precancerous lesion that is associated with an elevated risk of gastric carcinogenesis. Weiwei Decoction (WWD) is a promising traditional Chinese herbal formula widely employed in clinical for treating IM. Previous studies suggested the potential involvement of the olfactomedin 4 (OLFM4)/nucleotide-binding oligomerization domain 1 (NOD1)/caudal-type homeobox gene 2 (CDX2) signaling pathway in IM regulation.

AIM

To verify the regulation of the OLFM4/NOD1/CDX2 pathway in IM, specifically investigating WWD’s effectiveness on IM through this pathway.

METHODS

Immunohistochemistry for OLFM4, NOD1, and CDX2 was conducted on tissue microarray. GES-1 cells treated with chenodeoxycholic acid were utilized as IM cell models. OLFM4 short hairpin RNA (shRNA), NOD1 shRNA, and OLFM4 pcDNA were transfected to clarify the pathway regulatory relationships. Protein interactions were validated by co-immunoprecipitation. To explore WWD’s pharmacological actions, IM rat models were induced using N-methyl-N’-nitro-N-nitrosoguanidine followed by WWD gavage. Gastric cells were treated with WWD-medicated serum. Cytokines and chemokines content were assessed by enzyme-linked immunosorbent assay and quantitative reverse transcription polymerase chain reaction.

RESULTS

The OLFM4/NOD1/CDX2 axis was a characteristic of IM. OLFM4 exhibited direct binding and subsequent down-regulation of NOD1, thereby sustaining the activation of CDX2 and promoting the progression of IM. WWD improved gastric mucosal histological lesions while suppressing intestinal markers KLF transcription factor 4, villin 1, and MUCIN 2 expression in IM rats. Regarding pharmacological actions, WWD suppressed OLFM4 and restored NOD1 expression, consequently reducing CDX2 at the mRNA and protein levels in IM rats. Parallel regulatory mechanisms were observed at the protein level in IM cells treated with WWD-medicated serum. Furthermore, WWD-medicated serum treatment strengthened OLFM4 and NOD1 interaction. In case of anti-inflammatory, WWD restrained interleukin (IL)-6, interferon-gamma, IL-17, macrophage chemoattractant protein-1, macrophage inflammatory protein 1 alpha content in IM rat serum. WWD-medicated serum inhibited tumor necrosis factor alpha, IL-6, IL-8 transcriptions in IM cells.

CONCLUSION

The OLFM4/NOD1/CDX2 pathway is involved in the regulation of IM. WWD exerts its therapeutic efficacy on IM through the pathway, additionally attenuating the inflammatory response.

Keywords: Gastric intestinal metaplasia; Weiwei Decoction; Olfactomedin 4; Nucleotide-binding oligomerization domain 1; Caudal-type homeobox gene 2; Gastric cancer

Core Tip: Gastric intestinal metaplasia (IM) is a precancerous lesion that is associated with an elevated risk of gastric carcinogenesis. Weiwei Decoction (WWD) is a traditional Chinese herbal formula derived from Sijunzi Decoction that has been utilized to treat gastric disease for thousands of years. Nowadays, WWD is widely employed in clinical for treating IM. Previous studies suggested the potential involvement of the olfactomedin 4 (OLFM4)/nucleotide-binding oligomerization domain 1 (NOD1)/caudal-type homeobox gene 2 (CDX2) pathway in IM regulation. In this study, we preliminarily validated the pivotal role of the OLFM4/NOD1/CDX2 signaling pathway in regulating gastric IM. Focusing on this pathway, our investigation centered on the therapeutic effects of WWD against gastric IM.