Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 28, 2025; 31(16): 104920
Published online Apr 28, 2025. doi: 10.3748/wjg.v31.i16.104920
Interventional effect of hesperetin on N-methyl-N’-nitro-N-nitrosoguanidine-induced exosomal circ008274 in affecting normal cells to promote gastric carcinogenesis
Zhao-Feng Liang, Yu-Meng Xu, Jia-Jia Song, Zi-Han Gao, Hui Qian, Xue-Zhong Xu
Zhao-Feng Liang, Xue-Zhong Xu, Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated with Jiangsu University, Changzhou 213017, Jiangsu Province, China
Zhao-Feng Liang, Yu-Meng Xu, Jia-Jia Song, Zi-Han Gao, Hui Qian, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang 212013, Jiangsu Province, China
Co-first authors: Zhao-Feng Liang and Yu-Meng Xu.
Co-corresponding authors: Zhao-Feng Liang and Xue-Zhong Xu.
Author contributions: Xu YM and Liang ZF wrote the manuscript; Xu YM, Song JJ, and Gao ZH conducted the data analyses; Xu YM prepared the figures; Xu XZ, Qian H, and Liang ZF contributed to the editing and revision of the manuscript; All authors reviewed the manuscript.
Supported by the National Natural Science Foundation of China, No. 81602883; Technology Development Project of Jiangsu University, No. 20220516; and Postgraduate Research and Practice Innovation Program of Jiangsu Province, No. KYCX233765.
Institutional review board statement: This study was exclusively focused on cellular research and did not involve animal models or human samples. This study was reviewed and approved by the Wujin Hospital Affiliated with Jiangsu University Institution Review Board.
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
Data sharing statement: All data generated or analyzed in this study are included in this published article. Dataset available from the first author at liangzhaofeng@ujs.edu.cn. Participants gave informed consent for data sharing.
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: Zhao-Feng Liang, MD, Doctor, Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated with Jiangsu University, No. 2 Yongning North Road, Tianning District, Changzhou 213017, Jiangsu Province, China. liangzhaofeng@ujs.edu.cn
Received: January 10, 2025
Revised: February 25, 2025
Accepted: April 7, 2025
Published online: April 28, 2025
Processing time: 111 Days and 1.6 Hours
Abstract
BACKGROUND

Hesperetin, a flavonoid predominantly present in citrus fruits, exhibits significant intervention effects on both the initiation and progression of gastric cancer. However, the specific mechanisms underlying this effect remain unclear.

AIM

To investigate the interventional role of hesperetin on N-methyl-N’-nitro-N-nitrosoguanidine (MNNG)-induced exosomes in inducing gastric carcinogenesis.

METHODS

Bioinformatics technology was used to identify the critical molecular components underlying hesperetin-mediated inhibition of MNNG induced gastric carcinogenesis through exosomal circular RNA. Biological experiments were conducted to validate these findings.

RESULTS

Exosomes derived from TGES-1 cells (TGES-1-EX) significantly enhanced the proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and stemness of GES-1 cells. The oncogenic potential of TGES-1-EX was significantly diminished following hesperetin pretreatment. TGES-1-EX with overexpressed or knocked down circ0008274 was extracted and GES-1 cells were treated in combination with hesperetin or alone. Our investigation revealed that hesperetin exerted significant inhibitory effects on MNNG-induced gastric carcinogenesis by exosomal circ0008274. Bioinformatics prediction identified microRNA (miR)-526b-5p as a potential miRNA binding to circ0008274. Functional experiments demonstrated that hesperetin may mediate its intervention in MNNG-induced gastric cancer initiation by targeting miR-526b-5p through exosomal circ0008274. TGES-1-EX circ0008274 promoted the proliferation, EMT, and cancer stem cell-like characteristics in GES-1 cells through miR-526b-5p-mediated regulatory mechanisms.

CONCLUSION

Hesperetin exerted an interventional effect on the gastric carcinogenesis process, particularly through the modulation of exosomal circ0008274 and its interaction with miR-526b-5p.

Keywords: Hesperetin; Gastric cancer; N-methyl-N’-nitro-N-nitrosoguanidine; Exosomes; Circ0008274

Core Tip: Hesperetin, a citrus flavonoid, shows potential in inhibiting gastric cancer initiation and progression, but via unclear mechanisms. This study explored its role in countering N-methyl-N’-nitro-N-nitrosoguanidine-induced gastric carcinogenesis mediated by exosomal circular RNA. Bioinformatics and biological experiments revealed that exosomes from TGES-1 cells enhanced GES-1 cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and stemness, but hesperetin pretreatment significantly reduced these effects. Hesperetin targeted exosomal circ0008274, which interacts with microRNA-526b-5p, to inhibit cancer-inducing properties. Overexpression or knockdown of circ0008274 confirmed its role in promoting GES-1 cell proliferation, EMT, and stemness via miR-526b-5p. Hesperetin intervenes in gastric carcinogenesis by modulating the exosomal circ0008274/miR-526b-5p axis.