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基于非靶向代谢组学研究和网络药理学分析探讨四君子汤通过m6A甲基转移酶METTL14抑制胃癌转移的机制

The Mechanism of Sijunzi Decoction Suppresses Gastric Cancer Metastasis via the m6A Methyltransferase METTL14 Based on Untargeted Metabolomics Studies and Network Pharmacology Analysis.

作者信息

Li Xiangnan, Zhao Linlin, Wang Jiluan, Ma Tianchi, Zhou Jing, Bian Yue, Guo Junfu

机构信息

Teaching and Experiment Center, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, People's Republic of China.

Shenyang Key Laboratory for TCM Emotional Disorder, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, People's Republic of China.

出版信息

Drug Des Devel Ther. 2025 Mar 31;19:2369-2392. doi: 10.2147/DDDT.S506702. eCollection 2025.

DOI:10.2147/DDDT.S506702
PMID:40190808
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11970285/
Abstract

BACKGROUND

Sijunzi Decoction (SJZ), a Traditional Chinese Medicine (TCM) formula, is renowned for its capacity to fortify Qi and enhance spleen function. However, additional research is necessary to comprehend the mechanisms beneath the therapeutic potential of SJZ in gastric cancer.

OBJECTIVE

This research endeavored to analyze how SJZ treats gastric cancer using network pharmacology and experimental validation.

METHODS

Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and network pharmacology were applied to systemically clarify the mechanism of SJZ against gastric cancer. We used a xenograft tumor model of gastric cancer and gastric cancer cell lines to explore the effect of SJZ on N6-methyladenosine (m6A) modification. Cell transfection, plate clone formation, scratch migration, and transwell assays were performed in gastric cancer cell lines. The expression levels of m6A enzymes and epithelial-mesenchymal transition (EMT) markers were assessed by Quantitative real-time reverse transcription (RT-qPCR) and Western blotting.

RESULTS

The results revealed 511 active components and 196 targets of SJZ, with 167 targets associated with gastric cancer therapy. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis disclosed notable enrichment of pathways related to cancer, metabolism, and immunity. The protein-protein interaction (PPI) network comprised 274 nodes and 2902 edges, whereas the herbal component-target protein-pathway-disease network included 107 nodes and 345 edges, identifying four components with more than 20 putative targets. Experimental assays demonstrated a significant decrease in METTL3 expression following SJZ treatment, whereas the expression level of METTL14 was markedly elevated in the SJZ group across both gastric cancer cell lines and gastric cancer tissues derived from a mouse model (<0.01, <0.001, or <0.05). SJZ inhibited clone formation, migration, and invasion of gastric cancer cells, and EGFR and Vimentin expression via METTL14 (<0.05, <0.01, or <0.001).

CONCLUSION

METTL14 appears integral to the inhibition of EMT by SJZ as a treatment for gastric cancer.

摘要

背景

四君子汤（SJZ）是一种中药配方，以其补气健脾的功效而闻名。然而，需要进一步研究以了解SJZ治疗胃癌的潜在机制。

目的

本研究旨在通过网络药理学和实验验证分析SJZ治疗胃癌的方式。

方法

采用液相色谱-串联质谱联用（LC-MS/MS）和网络药理学方法系统阐明SJZ抗胃癌的机制。我们使用胃癌异种移植瘤模型和胃癌细胞系来探究SJZ对N6-甲基腺苷（m6A）修饰的影响。在胃癌细胞系中进行细胞转染、平板克隆形成、划痕迁移和Transwell实验。通过定量实时逆转录（RT-qPCR）和蛋白质免疫印迹法评估m6A酶和上皮-间质转化（EMT）标志物的表达水平。

结果

结果显示SJZ有511种活性成分和196个靶点，其中167个靶点与胃癌治疗相关。京都基因与基因组百科全书（KEGG）富集分析表明，与癌症、代谢和免疫相关的通路显著富集。蛋白质-蛋白质相互作用（PPI）网络由274个节点和2902条边组成，而草药成分-靶点蛋白-通路-疾病网络包含107个节点和345条边，确定了四种具有20多个推定靶点的成分。实验分析表明，SJZ处理后METTL3表达显著降低，而在胃癌细胞系和小鼠模型来源的胃癌组织中，SJZ组的METTL14表达水平均显著升高（<0.01、<0.001或<0.05）。SJZ通过METTL14抑制胃癌细胞的克隆形成、迁移和侵袭以及EGFR和波形蛋白的表达（<0.05、<0.01或<0.001）。

结论

METTL14似乎是SJZ作为胃癌治疗药物抑制EMT所必需的。

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