Clinical and Translational Research
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. May 15, 2024; 16(5): 1925-1946
Published online May 15, 2024. doi: 10.4251/wjgo.v16.i5.1925
METTL5 promotes gastric cancer progression via sphingomyelin metabolism
Ya-Qiong Zhang, Jian Li, Zhe Qin, De-Ming Li, Fang-Zhou Ye, Song-Hua Bei, Xiao-Hong Zhang, Li Feng
Ya-Qiong Zhang, Jian Li, Zhe Qin, De-Ming Li, Fang-Zhou Ye, Song-Hua Bei, Xiao-Hong Zhang, Li Feng, Endoscopy Center, Minhang Hospital Affiliated to Fudan University, Shanghai 201100, China
Co-corresponding authors: Xiao-Hong Zhang and Li Feng.
Author contributions: Zhang YQ and Feng L designed the framework of the entire article; Zhang XH and Feng L provided funding support; Zhang YQ completed the entire manuscript; and Qin Z, Li DM, Ye FZ, Bei SH completed the experimental part of the article. All authors were involved in the critical review of the results and have contributed to, read, and approved the final manuscript. Zhang XH and Feng L contributed equally to this work as co-corresponding authors. The reasons for designating Zhang XH and Feng L as co-corresponding authors are as followed. Firstly, the research funding was jointly provided by Zhang XH and Feng L; Secondly, Feng L provided extensive guidance on the epidemiology and clinical treatment status of gastric cancer at the beginning of the project design; Zhang XH provided extensive guidance in analyzing experimental data and answering questions. So, Zhang XH and Feng L can serve as co-corresponding authors of this manuscript.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of Minhang Hospital Affiliated to Fudan University.
Informed consent statement: All study participants or their legal guardian provided informed written consent about personal and medical data collection prior to study enrolment.
Conflict-of-interest statement: This manuscript has not been published or presented elsewhere in part or in entirety and is not under consideration by another journal. There are no conflicts of interest to declare.
Data sharing statement: No additional data are available.
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: Li Feng, PhD, Chief Physician, Endoscopy Center, Minhang Hospital Affiliated to Fudan University, No. 138 Medical College Road, Xuhui District, Shanghai 201100, China. feng_li@fudan.edu.cn
Received: December 11, 2023
Peer-review started: December 11, 2023
First decision: December 29, 2023
Revised: January 9, 2024
Accepted: February 19, 2024
Article in press: February 19, 2024
Published online: May 15, 2024
Abstract
BACKGROUND

The treatment of gastric cancer (GC) has caused an enormous social burden worldwide. Accumulating studies have reported that N6-methyladenosine (m6A) is closely related to tumor progression. METTL5 is a m6A methyltransferase that plays a pivotal role in maintaining the metabolic stability of cells. However, its aberrant regulation in GC has not been fully elucidated.

AIM

To excavate the role of METTL5 in the development of GC.

METHODS

METTL5 expression and clinicopathological characteristics were analyzed via The Cancer Genome Atlas dataset and further verified via immunohistochemistry, western blotting and real-time quantitative polymerase chain reaction in tissue microarrays and clinical samples. The tumor-promoting effect of METTL5 on HGC-27 and AGS cells was explored in vitro by Cell Counting Kit-8 assays, colony formation assays, scratch healing assays, transwell assays and flow cytometry. The tumor-promoting role of METTL5 in vivo was evaluated in a xenograft tumor model. The EpiQuik m6A RNA Methylation Quantification Kit was used for m6A quantification. Next, liquid chromatography-mass spectrometry was used to evaluate the association between METTL5 and sphingomyelin metabolism, which was confirmed by Enzyme-linked immunosorbent assay and rescue tests. In addition, we investigated whether METTL5 affects the sensitivity of GC cells to cisplatin via colony formation and transwell experiments.

RESULTS

Our research revealed substantial upregulation of METTL5, which suggested a poor prognosis of GC patients. Increased METTL5 expression indicated distant lymph node metastasis, advanced cancer stage and pathological grade. An increased level of METTL5 correlated with a high degree of m6A methylation. METTL5 markedly promotes the proliferation, migration, and invasion of GC cells in vitro. METTL5 also promotes the growth of GC in animal models. METTL5 knockdown resulted in significant changes in sphingomyelin metabolism, which implies that METTL5 may impact the development of GC via sphingomyelin metabolism. In addition, high METTL5 expression led to cisplatin resistance.

CONCLUSION

METTL5 was found to be an oncogenic driver of GC and may be a new target for therapy since it facilitates GC carcinogenesis through sphingomyelin metabolism and cisplatin resistance.

Keywords: Gastric cancer, METTL5, Sphingomyelin metabolism, Cisplatin

Core Tip: This study revealed that increased METTL5 expression indicates an unfavorable prognosis and advanced clinical stage in patients with gastric cancer (GC). METTL5 markedly promoted the proliferation, migration, and invasion of GC cells. METTL5 stimulated the metabolism of sphingomyelin to induce GC tumorigenesis. In addition, METTL5 weakened the sensitivity of GC cells to cisplatin, serving as a novel target for GC treatment.