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): 3270-3283
Published online Jul 15, 2024. doi: 10.4251/wjgo.v16.i7.3270
N6-methyladenosine modification of hypoxia-inducible factor-1α regulates Helicobacter pylori-associated gastric cancer via the PI3K/AKT pathway
Tong-Yan An, Quan-Man Hu, Peng Ni, Yan-Qiao Hua, Di Wang, Guang-Cai Duan, Shuai-Yin Chen, Bin Jia
Tong-Yan An, Quan-Man Hu, Peng Ni, Yan-Qiao Hua, Di Wang, Guang-Cai Duan, Shuai-Yin Chen, Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
Bin Jia, Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
Co-corresponding authors: Shuai-Yin Chen and Bin Jia.
Author contributions: An TY, Chen SY, and Jia B designed the study; An TY, Hu QM, and Ni P carried out the research and statistical analyses; An TY drafted the manuscript; Hua YQ, Wang D, Duan GC, and Chen SY contributed to the review and editing of the manuscript; all authors have read and approved the final manuscript.
Supported by The Key Research and Development and Promotion Special Project of Henan Province, No. 222102310069; National Natural Science Foundation of China, No. 82073618.
Institutional review board statement: The study was conducted in vitro and did not involve human or animal subjects.
Institutional animal care and use committee statement: The study was conducted in vitro and did not involve human or animal subjects.
Conflict-of-interest statement: The authors declare no competing interests for this article.
Data sharing statement: The experimental data that support the findings of this study are available from the corresponding author at sychen@zzu.edu.cn.
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: Shuai-Yin Chen, MD, PhD, Associate Professor, Department of Epidemiology, College of Public Health, Zhengzhou University, No. 100 Kexue Road, Zhengzhou 450001, Henan Province, China. sychen@zzu.edu.cn
Received: March 10, 2024
Revised: May 9, 2024
Accepted: May 20, 2024
Published online: July 15, 2024
Processing time: 124 Days and 4.9 Hours
Abstract
BACKGROUND

Helicobacter pylori (H. pylori) colonizes the human gastric mucosa and is implicated in the development of gastric cancer (GC). The tumor microenvironment is characterized by hypoxia, where hypoxia-inducible factor-1α (HIF-1α) plays a key role as a transcription factor, but the mechanisms underlying H. pylori-induced HIF-1α expression and carcinogenesis remain unclear.

AIM

To explore the underlying mechanism of H. pylori-induced HIF-1α expression in promoting the malignant biological behavior of gastric epithelial cells (GES-1).

METHODS

The study was conducted with human GES-1 cells in vitro. Relative protein levels of methyltransferase-like protein 14 (METTL14), HIF-1α, main proteins of the PI3K/AKT pathway, epithelial-mesenchymal transition (EMT) biomarkers, and invasion indicators were detected by Western blot. Relative mRNA levels of METTL14 and HIF-1α were detected by quantitative reverse transcription-polymerase chain reaction. mRNA stability was evaluated using actinomycin D, and the interaction between METTL14 and HIF-1α was confirmed by immunofluorescence staining. Cell proliferation and migration were evaluated by cell counting kit-8 assay and wound healing assay, respectively.

RESULTS

H. pylori promoted HIF-1α expression and activated the PI3K/AKT pathway. Notably, METTL14 was downregulated in H. pylori-infected gastric mucosal epithelial cells and positively regulated HIF-1α expression. Functional experiments showed that the overexpression of HIF-1α or knockdown of METTL14 enhanced the activity of the PI3K/AKT pathway, thereby driving a series of malignant transformation, such as EMT and cell proliferation, migration, and invasion. By contrast, the knockdown of HIF-1α or overexpression of METTL14 had an opposite effect.

CONCLUSION

H. pylori-induced underexpression of METTL14 promotes the translation of HIF-1α and accelerates tumor progression by activating the PI3K/AKT pathway. These results provide novel insights into the carcinogenesis of GC.

Keywords: Helicobacter pylori, Gastric cancer, Methyltransferase-like protein 14, Hypoxia-inducible factor-1α, N6-methyladenosine, PI3K/AKT pathway

Core Tip:Helicobacter pylori (H. pylori) is the most significant risk factor for gastric cancer. Studies have shown that hypoxia-inducible factor-1α (HIF-1α) is highly expressed in tumors, enabling them to adapt to hypoxic microenvironment and promoting malignant behavior. However, the pathogenesis of HIF-1α in H. pylori infection remains unclear. We found that methyltransferase-like protein 14 acts as a molecular switch of H. pylori-induced HIF-1α expression and regulates the malignant behavior of gastric epithelial cells through the PI3K/AKT pathway. This study is the first to explore the mechanism by which H. pylori induces HIF-1α expression from the perspective of N6-methyladenosine modification.