Basic Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Jul 15, 2021; 13(7): 693-705
Published online Jul 15, 2021. doi: 10.4251/wjgo.v13.i7.693
Cryptotanshinone inhibits cytotoxin-associated gene A-associated development of gastric cancer and mucosal erosions
Zhang-Ming Chen, Jie Hu, Yuan-Min Xu, Wei He, Lei Meng, Ting Huang, Song-Cheng Ying, Zhe Jiang, A-Man Xu
Zhang-Ming Chen, Jie Hu, A-Man Xu, Department of General Surgery, Fourth Affiliated Hospital of Anhui Medical University, Hefei 230001, Anhui Province, China
Yuan-Min Xu, Lei Meng, Zhe Jiang, Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China
Wei He, Department of Surgery, East District of First Affiliated Hospital of Anhui Medical University (Feidong People's Hospital), Hefei 230001, Anhui Province, China
Ting Huang, Song-Cheng Ying, Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui Province, China
Author contributions: Chen ZM, Hu J, and Xu YM contributed equally to this work; Xu AM, Jiang Z, and Ying SC designed the study; Chen ZM, Hu J, and Xu YM conducted the experiments and analyzed the data; He W, Meng L, and Huang T provided materials and participated in the data analyses; Chen ZM and Jiang Z wrote the manuscript; Ying SC and Xu AM participated in the revision of the manuscript.
Supported by National Natural Science Foundation of China, No. 81572350
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board of First Affiliated Hospital of Anhui Medical University.
Institutional animal care and use committee statement: The protocol for the animal experiments was approved by the Laboratory Animal Ethics Committee of Anhui Medical University.
Informed consent statement: All patients signed the informed consent.
Conflict-of-interest statement: The authors declare that they have no competing interests.
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: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: A-Man Xu, MD, PhD, Professor, Department of General Surgery, Fourth Affiliated Hospital of Anhui Medical University, No. 100 Huaihai Avenue, Hefei 230001, Anhui Province, China. xamhwx@163.com
Received: March 4, 2021
Peer-review started: March 4, 2021
First decision: April 17, 2021
Revised: April 19, 2021
Accepted: June 1, 2021
Article in press: June 1, 2021
Published online: July 15, 2021
Processing time: 127 Days and 19 Hours
Abstract
BACKGROUND

Approximately 90% of new cases of noncardiac gastric cancer (GC) are related to Helicobacter pylori (H. pylori), and cytotoxin-associated gene A (CagA) is one of the main pathogenic factors. Recent studies have shown that the pharmacological effects of cryptotanshinone (CTS) can be used to treat a variety of tumors. However, the effects of CTS on H. pylori, especially CagA+ strain-induced gastric mucosal lesions, on the development of GC is unknown.

AIM

To assess the role of CTS in CagA-induced proliferation and metastasis of GC cells, and determine if CagA+ H. pylori strains causes pathological changes in the gastric mucosa of mice.

METHODS

The effects of CTS on the proliferation of GC cells were assessed using the Cell Counting Kit-8 (CCK-8) assay, and the abnormal growth, migration and invasion caused by CagA were detected by CCK-8 and transwell assays. After transfection with pSR-HA-CagA and treatment with CTS, proliferation and metastasis were evaluated by CCK-8 and transwell assays, respectively, and the expression of Src homology 2 (SH2) domain–containing phosphatase 2 (SHP2) and phosphorylated SHP2 (p-SHP2) was detected using western blotting in AGS cells. The enzyme-linked immunosorbent assay was used to determine the immunoglobulin G (IgG) level against CagA in patient serum. Mice were divided into four groups and administered H. pylori strains (CagA+ or CagA-) and CTS (or PBS) intragastrically, and establishment of the chronic infection model was verified using polymerase chain reaction and sequencing of isolated strains. Hematoxylin and eosin staining was used to assess mucosal erosion in the stomach and toxicity to the liver and kidney.

RESULTS

CTS inhibited the growth of GC cells in dose- and time-dependent manners. Overexpression of CagA promoted the growth, migration, and invasion of GC cells. Importantly, we demonstrated that CTS significantly inhibited the CagA-induced abnormal proliferation, migration, and invasion of GC cells. Moreover, the expression of p-SHP2 protein in tumor tissue was related to the expression of IgG against CagA in the serum of GC patients. Additionally, CTS suppressed the protein expression levels of both SHP2 and p-SHP2 in GC cells. CTS suppressed CagA+ H. pylori strain-induced mucosal erosion in the stomach of mice but had no obvious effects on the CagA- H. pylori strain group.

CONCLUSION

CTS inhibited CagA-induced proliferation and the epithelial-mesenchymal transition of GC cells in vitro, and CagA+ H. pylori strains caused mucosal erosions of the stomach in vivo by decreasing the protein expression of SHP2.

Keywords: Cytotoxin associated gene A; SHP2; Cryptotanshinone; Helicobacter pylori; Chronic infection model

Core Tip: Cryptotanshinone inhibited cytotoxin-associated gene A (CagA)-induced proliferation and the epithelial-mesenchymal transition of gastric cancer cells in vitro, and Helicobacter pylori (H. pylori)CagA-positive strains caused mucosal erosions of stomach in vivo by decreasing the expression of SHP2 protein, which could be an effective drug in treating H. pylori infection.