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Li X, Zhao L, Wang J, Ma T, Zhou J, Bian Y, Guo J. The Mechanism of Sijunzi Decoction Suppresses Gastric Cancer Metastasis via the m6A Methyltransferase METTL14 Based on Untargeted Metabolomics Studies and Network Pharmacology Analysis. Drug Des Devel Ther 2025; 19:2369-2392. [PMID: 40190808 PMCID: PMC11970285 DOI: 10.2147/dddt.s506702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 03/18/2025] [Indexed: 04/09/2025] Open
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 (P<0.01, P<0.001, or P<0.05). SJZ inhibited clone formation, migration, and invasion of gastric cancer cells, and EGFR and Vimentin expression via METTL14 (P<0.05, P<0.01, or P<0.001). Conclusion METTL14 appears integral to the inhibition of EMT by SJZ as a treatment for gastric cancer.
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MESH Headings
- Stomach Neoplasms/drug therapy
- Stomach Neoplasms/pathology
- Stomach Neoplasms/metabolism
- Humans
- Methyltransferases/metabolism
- Methyltransferases/antagonists & inhibitors
- Methyltransferases/genetics
- Network Pharmacology
- Drugs, Chinese Herbal/pharmacology
- Drugs, Chinese Herbal/chemistry
- Animals
- Metabolomics
- Mice
- Cell Proliferation/drug effects
- Epithelial-Mesenchymal Transition/drug effects
- Drug Screening Assays, Antitumor
- Cell Movement/drug effects
- Antineoplastic Agents, Phytogenic/pharmacology
- Antineoplastic Agents, Phytogenic/chemistry
- Cell Line, Tumor
- Tumor Cells, Cultured
- Mice, Nude
- Mice, Inbred BALB C
- Neoplasms, Experimental/drug therapy
- Neoplasms, Experimental/pathology
- Neoplasms, Experimental/metabolism
- Dose-Response Relationship, Drug
- Adenosine/analogs & derivatives
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Affiliation(s)
- Xiangnan Li
- 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
| | - Linlin Zhao
- College of Chinese Medicine Integrated with Western Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, People’s Republic of China
| | - Jiluan Wang
- College of Chinese Medicine Integrated with Western Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, People’s Republic of China
| | - Tianchi Ma
- 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
| | - Jing Zhou
- 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
| | - Yue Bian
- Department of Nursing, Shenyang Medical College, Shenyang, Liaoning, People’s Republic of China
| | - Junfu Guo
- 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
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Li P, Fang X, Huang D. Exploring m6A modifications in gastric cancer: from molecular mechanisms to clinical applications. Eur J Med Res 2025; 30:98. [PMID: 39940056 PMCID: PMC11823136 DOI: 10.1186/s40001-025-02353-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 02/03/2025] [Indexed: 02/14/2025] Open
Abstract
The significance of m6A modifications in several biological processes has been increasingly recognized, particularly in the context of cancer. For instance, m6A modifications in gastric cancer (GC) have been significantly implicated in tumor progression, metastasis, and treatment resistance. GC is characterized by the differential expression of m6A regulators. High expression writers such as METTL3 and WTAP are associated with poor prognosis and aggressive clinical features. Conversely, low expression of METTL14 is linked to worse clinical outcomes, whereas elevated levels of demethylases, such as FTO and ALKBH5, correlate with better survival rates. These m6A regulators influence several cellular biological functions, including proliferation, invasion, migration, glycolysis, and chemotherapy resistance, thereby affecting tumor growth and therapeutic outcomes. The assessment of m6A modification patterns and the expression profiles of m6A-related genes hold substantial potential for improving the clinical diagnosis and treatment of GC. In this review, we provide an updated and comprehensive summary of the role of m6A modifications in GC, emphasizing their molecular mechanisms, clinical significance, and translational applications in developing novel diagnostic and therapeutic strategies.
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Affiliation(s)
- Penghui Li
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, 471000, Henan, China.
| | - Xiangjie Fang
- Department of General Surgery, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453100, Henan, China
| | - Di Huang
- Department of Child Health Care, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
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3
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Yan T, Wang Q, Liu Y. METTL3 stabilizes SERPINE2 via the m6A modification to drive the malignant progression of gastric signet ring cell carcinoma. Transl Cancer Res 2025; 14:78-92. [PMID: 39974426 PMCID: PMC11833417 DOI: 10.21037/tcr-24-896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 12/04/2024] [Indexed: 02/21/2025]
Abstract
Background Gastric signet ring cell carcinoma (GSRCC) is a highly lethal malignancy. Serpin family E member 2 (SERPINE2) is a pro-tumorigenic factor in cancer. Here, we sought to define the role of SERPINE2 in the pathogenesis of GSRCC. Methods Messenger RNA (mRNA) expression was analyzed by quantitative polymerase chain reaction (PCR). Protein expression was tested by immunohistochemistry (IHC) and immunoblot assays. Proliferation was assessed by 5-ethynyl-2'-deoxyuridine (EdU) assay, and invasion and migration were detected by transwell assay. Tube formation assay was used to test the influence on angiogenesis. Cell apoptosis and M2 macrophage polarization were evaluated by flow cytometry. The methyltransferase-like 3 (METTL3)-SERPINE2 relationship was analyzed by RNA immunoprecipitation (RIP), luciferase, and mRNA stabilization assays. Xenograft experiments were used for assessment of METTL3's influence on tumorigenicity of GSRCC cells. Results SERPINE2 and METTL3 levels were upregulated in human GSRCC. Functionally, SERPINE2 depletion enhanced apoptosis of GSRCC cells and diminished their proliferative, migratory and invasive capacities in vitro. Moreover, SERPINE2 depletion suppressed tube formation ability of human umbilical vein endothelial cells (HUVECs) and M2 polarization of THP-1-derived macrophages. Mechanistically, METTL3 induced SERPINE2 upregulation by enhancing SERPINE2 mRNA stabilization. Our rescue experiments indicated that the effects of METTL3 depletion on cell phenotypes were due to the reduction of SERPINE2 expression. Additionally, METTL3 deficiency inhibited GSRCC xenograft growth in vivo. Conclusions Our study defines the significant roles of the METTL3/SERPINE2 axis as an epigenetic mechanism in GSRCC progression. Our work may have diagnostic and/or therapeutic applications in GSRCC.
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Affiliation(s)
- Tan Yan
- Department of Oncology Surgery, the Nuclear Industry 215 Hospital, Hospital of Shaanxi Province, Xianyang, China
| | - Qian Wang
- Department of Oncology Surgery, the Nuclear Industry 215 Hospital, Hospital of Shaanxi Province, Xianyang, China
| | - Yuhui Liu
- Department of Pharmacy, the Nuclear Industry 215 Hospital, Hospital of Shaanxi Province, Xianyang, China
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4
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Li N, Wei X, Dai J, Yang J, Xiong S. METTL3: a multifunctional regulator in diseases. Mol Cell Biochem 2025:10.1007/s11010-025-05208-z. [PMID: 39853661 DOI: 10.1007/s11010-025-05208-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 01/04/2025] [Indexed: 01/26/2025]
Abstract
N6-methyladenosine (m6A) methylation is the most prevalent and abundant internal modification of mRNAs and is catalyzed by the methyltransferase complex. Methyltransferase-like 3 (METTL3), the best-known m6A methyltransferase, has been confirmed to function as a multifunctional regulator in the reversible epitranscriptome modulation of m6A modification according to follow-up studies. Accumulating evidence in recent years has shown that METTL3 can regulate a variety of functional genes, that aberrant expression of METTL3 is usually associated with many pathological conditions, and that its expression regulatory mechanism is related mainly to its methyltransferase activity or mRNA posttranslational modification. In this review, we discuss the regulatory functions of METTL3 in various diseases, including metabolic diseases, cardiovascular diseases, and cancer. We focus mainly on recent progress in identifying the downstream target genes of METTL3 and its underlying molecular mechanisms and regulators in the above systems. Studies have revealed that the use of METTL3 as a therapeutic target and a new diagnostic biomarker has broad prospects. We hope that this review can serve as a reference for further studies.
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Affiliation(s)
- Na Li
- Division of Cardiothoracic and Vascular Surgery, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiang Wei
- Division of Cardiothoracic and Vascular Surgery, Sino-Swiss Heart-Lung Transplantation Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jian Dai
- Department of Critical Care Medicine, Wuhan Wuchang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei, China
| | - Jinfeng Yang
- Department of Medical Affairs, Wuhan Wuchang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei, China.
| | - Sizheng Xiong
- Department of Vascular Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
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Chen S, He J, Gao H, Gao X, Dai L, Chen J, Sha Z. ADAMTS7 Enhances Gastric Cancer Growth and Metastasis by Triggering the NF-κB Signaling Pathway. J Cancer 2025; 16:1008-1019. [PMID: 39781347 PMCID: PMC11705055 DOI: 10.7150/jca.103093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Accepted: 12/14/2024] [Indexed: 01/12/2025] Open
Abstract
The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family of metalloproteinases plays a vital role in various biological and pathological processes, including tissue remodeling, angiogenesis, and cancer progression. Among the 19 ADAMTS family members, our research focused on ADAMTS7, which exhibited significant overexpression in gastric cancer (GC). This overexpression was strongly correlated with poor clinical outcomes, including reduced overall survival and heightened metastatic potential. To investigate the role of ADAMTS7 in GC, we employed an integrated approach encompassing bioinformatics analysis, Western blotting, immunofluorescence, as well as in vitro and in vivo functional analyses. Our results showed that silencing ADAMTS7 expression significantly inhibited the proliferation, migration, and invasion of GC cells, and furthermore, silencing ADAMTS7 significantly inhibited the growth and metastasis of tumour cells in vivo in nude mice, highlighting its critical role in driving the malignant behaviour of GC cells. Further mechanistic studies identified the NF-κB signaling pathway as a key downstream target of ADAMTS7, with ADAMTS7 silencing resulting in a notable reduction in NF-κB pathway activity. These findings establish ADAMTS7 as a significant contributor to the aggressiveness of GC and a pivotal activator of the NF-κB pathway, a major regulator of inflammation and tumor progression. Consequently, ADAMTS7 emerges as a promising therapeutic target and prognostic biomarker for GC. Our study opens new avenues for the development of targeted therapies aimed at inhibiting ADAMTS7 activity, thereby potentially improving treatment outcomes and survival rates for patients with GC.
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Affiliation(s)
- Shun Chen
- Department of Gastrointestinal Surgery, Affiliated Hospital and Medical School of Nantong University, Nantong 226001, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, China
- Nantong Key Laboratory of Gastrointestinal Oncology, Nantong, 226001, China
| | - Jiancheng He
- Department of Gastrointestinal Surgery, Affiliated Hospital and Medical School of Nantong University, Nantong 226001, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, China
- Nantong Key Laboratory of Gastrointestinal Oncology, Nantong, 226001, China
| | - Hanxu Gao
- Department of Gastrointestinal Surgery, Affiliated Hospital and Medical School of Nantong University, Nantong 226001, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, China
- Nantong Key Laboratory of Gastrointestinal Oncology, Nantong, 226001, China
| | - Xian Gao
- Department of Gastrointestinal Surgery, Affiliated Hospital and Medical School of Nantong University, Nantong 226001, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, China
- Nantong Key Laboratory of Gastrointestinal Oncology, Nantong, 226001, China
| | - Lingchen Dai
- Department of Gastrointestinal Surgery, Affiliated Hospital and Medical School of Nantong University, Nantong 226001, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, China
- Nantong Key Laboratory of Gastrointestinal Oncology, Nantong, 226001, China
| | - Junjie Chen
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, China
- Nantong Key Laboratory of Gastrointestinal Oncology, Nantong, 226001, China
| | - Zhenyu Sha
- High Quality Development Assessment Office, Affiliated Hospital of Nantong University, No 20, Xisi Road, Nantong 226001, China
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Qin L, Zeng X, Qiu X, Chen X, Liu S. The role of N6-methyladenosine modification in tumor angiogenesis. Front Oncol 2024; 14:1467850. [PMID: 39691597 PMCID: PMC11649548 DOI: 10.3389/fonc.2024.1467850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Accepted: 11/11/2024] [Indexed: 12/19/2024] Open
Abstract
Tumor angiogenesis is a characteristics of malignant cancer progression that facilitates cancer cell growth, diffusion and metastasis, and has an indispensable role in cancer development. N6-methyladenosine (m6A) is among the most prevalent internal modifications in eukaryotic RNAs, and has considerable influence on RNA metabolism, including its transcription, splicing, localization, translation, recognition, and degradation. The m6A modification is generated by m6A methyltransferases ("writers"), removed by m6A demethylases ("erasers"), and recognized by m6A-binding proteins ("readers"). There is accumulating evidence that abnormal m6A modification is involved in the pathogenesis of multiple diseases, including cancers, and promotes cancer occurrence, development, and progression through its considerable impact on oncoprotein expression. Furthermore, increasing studies have demonstrated that m6A modification can influence angiogenesis in cancers through multiple pathways to regulate malignant processes. In this review, we elaborate the role of m6A modification in tumor angiogenesis-related molecules and pathways in detail, providing insights into the interactions between m6A and tumor angiogenesis. Moreover, we describe how targeting m6A modification in combination with anti-angiogenesis drugs is expected to be a promising anti-tumor treatment strategy, with potential value for addressing the challenge of drug resistance.
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Affiliation(s)
| | | | | | | | - Shiquan Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical
University, Nanning, Guangxi, China
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7
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Yu Z, Yang Y. METTL3 as a potential therapeutic target in gastric cancer. Front Oncol 2024; 14:1483435. [PMID: 39678510 PMCID: PMC11638058 DOI: 10.3389/fonc.2024.1483435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 10/28/2024] [Indexed: 12/17/2024] Open
Abstract
Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. N6-methyladenosine (m6A) modification is the most prominent epigenetic modification of eukaryotic mRNAs, and methyltransferase-like 3 (METTL3), a core component of the methyltransferase complex, catalyzes m6A modification. The results of previous studies indicate that the expression level of METTL3 is significantly elevated in gastric cancer tissues and cells. In addition, fluctuations in m6A levels induced by METTL3 are closely associated with the malignant progression of tumors as well as the poor prognosis of patients with gastric cancer. In this review, we focus on the potential mechanism of METTL3 in gastric cancer, and through our analysis, we suggest that targeting METTL3 could be a new therapeutic tool for treating GC.
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Affiliation(s)
| | - Yang Yang
- The First Affiliated Hospital of Guangxi University Of Chinese Medicine,
Nanning, Guangxi, China
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8
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YuYan, Yuan E. Regulatory effect of N6-methyladenosine on tumor angiogenesis. Front Immunol 2024; 15:1453774. [PMID: 39295872 PMCID: PMC11408240 DOI: 10.3389/fimmu.2024.1453774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 08/19/2024] [Indexed: 09/21/2024] Open
Abstract
Previous studies have demonstrated that genetic alterations governing epigenetic processes frequently drive tumor development and that modifications in RNA may contribute to these alterations. In the 1970s, researchers discovered that N6-methyladenosine (m6A) is the most prevalent form of RNA modification in advanced eukaryotic messenger RNA (mRNA) and noncoding RNA (ncRNA). This modification is involved in nearly all stages of the RNA life cycle. M6A modification is regulated by enzymes known as m6A methyltransferases (writers) and demethylases (erasers). Numerous studies have indicated that m6A modification can impact cancer progression by regulating cancer-related biological functions. Tumor angiogenesis, an important and unregulated process, plays a pivotal role in tumor initiation, growth, and metastasis. The interaction between m6A and ncRNAs is widely recognized as a significant factor in proliferation and angiogenesis. Therefore, this article provides a comprehensive review of the regulatory mechanisms underlying m6A RNA modifications and ncRNAs in tumor angiogenesis, as well as the latest advancements in molecular targeted therapy. The aim of this study is to offer novel insights for clinical tumor therapy.
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Affiliation(s)
- YuYan
- Department of Laboratory Medicine, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Enwu Yuan
- Department of Laboratory Medicine, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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9
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Qu Y, Gao N, Zhang S, Gao L, He B, Wang C, Gong C, Shi Q, Li Z, Yang S, Xiao Y. Role of N6-methyladenosine RNA modification in cancer. MedComm (Beijing) 2024; 5:e715. [PMID: 39252821 PMCID: PMC11381670 DOI: 10.1002/mco2.715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 08/13/2024] [Accepted: 08/13/2024] [Indexed: 09/11/2024] Open
Abstract
N6-methyladenosine (m6A) is the most abundant modification of RNA in eukaryotic cells. Previous studies have shown that m6A is pivotal in diverse diseases especially cancer. m6A corelates with the initiation, progression, resistance, invasion, and metastasis of cancer. However, despite these insights, a comprehensive understanding of its specific roles and mechanisms within the complex landscape of cancer is still elusive. This review begins by outlining the key regulatory proteins of m6A modification and their posttranslational modifications (PTMs), as well as the role in chromatin accessibility and transcriptional activity within cancer cells. Additionally, it highlights that m6A modifications impact cancer progression by modulating programmed cell death mechanisms and affecting the tumor microenvironment through various cancer-associated immune cells. Furthermore, the review discusses how microorganisms can induce enduring epigenetic changes and oncogenic effect in microorganism-associated cancers by altering m6A modifications. Last, it delves into the role of m6A modification in cancer immunotherapy, encompassing RNA therapy, immune checkpoint blockade, cytokine therapy, adoptive cell transfer therapy, and direct targeting of m6A regulators. Overall, this review clarifies the multifaceted role of m6A modification in cancer and explores targeted therapies aimed at manipulating m6A modification, aiming to advance cancer research and improve patient outcomes.
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Affiliation(s)
- Yi Qu
- Department of Gastroenterology Xinqiao Hospital Army Medical University Chongqing China
| | - Nannan Gao
- Department of Gastroenterology Xinqiao Hospital Army Medical University Chongqing China
| | - Shengwei Zhang
- Department of Gastroenterology Xinqiao Hospital Army Medical University Chongqing China
| | - Limin Gao
- Department of Gastroenterology Xinqiao Hospital Army Medical University Chongqing China
| | - Bing He
- Department of Gastroenterology Xinqiao Hospital Army Medical University Chongqing China
| | - Chao Wang
- Department of Gastroenterology Xinqiao Hospital Army Medical University Chongqing China
| | - Chunli Gong
- Department of Gastroenterology Xinqiao Hospital Army Medical University Chongqing China
| | - Qiuyue Shi
- Department of Gastroenterology the First Affiliated Hospital of Guangxi Medical University Nanning Guangxi China
| | - Zhibin Li
- Department of Gastroenterology Xinqiao Hospital Army Medical University Chongqing China
| | - Shiming Yang
- Department of Gastroenterology Xinqiao Hospital Army Medical University Chongqing China
| | - Yufeng Xiao
- Department of Gastroenterology Xinqiao Hospital Army Medical University Chongqing China
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Zhao L, Li Q, Zhou T, Liu X, Guo J, Fang Q, Cao X, Geng Q, Yu Y, Zhang S, Deng T, Wang X, Jiao Y, Zhang M, Liu H, Tan H, Xiao C. Role of N6-methyladenosine in tumor neovascularization. Cell Death Dis 2024; 15:563. [PMID: 39098905 PMCID: PMC11298539 DOI: 10.1038/s41419-024-06931-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 07/14/2024] [Accepted: 07/22/2024] [Indexed: 08/06/2024]
Abstract
Tumor neovascularization is essential for the growth, invasion, and metastasis of tumors. Recent studies have highlighted the significant role of N6-methyladenosine (m6A) modification in regulating these processes. This review explores the mechanisms by which m6A influences tumor neovascularization, focusing on its impact on angiogenesis and vasculogenic mimicry (VM). We discuss the roles of m6A writers, erasers, and readers in modulating the stability and translation of angiogenic factors like vascular endothelial growth factor (VEGF), and their involvement in key signaling pathways such as PI3K/AKT, MAPK, and Hippo. Additionally, we outline the role of m6A in vascular-immune crosstalk. Finally, we discuss the current development of m6A inhibitors and their potential applications, along with the contribution of m6A to anti-angiogenic therapy resistance. Highlighting the therapeutic potential of targeting m6A regulators, this review provides novel insights into anti-angiogenic strategies and underscores the need for further research to fully exploit m6A modulation in cancer treatment. By understanding the intricate role of m6A in tumor neovascularization, we can develop more effective therapeutic approaches to inhibit tumor growth and overcome treatment resistance. Targeting m6A offers a novel approach to interfere with the tumor's ability to manipulate its microenvironment, enhancing the efficacy of existing treatments and providing new avenues for combating cancer progression.
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Affiliation(s)
- Lu Zhao
- Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China
- China-Japan Friendship Hospital, Capital Medical University, Beijing, China
| | - Qinshan Li
- Institute of Precision Medicine of Guizhou Province, Department of Obstetrics and Gynecology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550004, China
- Department of Clinical Biochemistry, School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, Guizhou, 550004, China
| | - Tongliang Zhou
- Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Xuan Liu
- Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Jing Guo
- Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Qing Fang
- Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Xiaoxue Cao
- Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing, China
| | - Qishun Geng
- Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing, China
| | - Yang Yu
- Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Songjie Zhang
- Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Tingting Deng
- Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Xing Wang
- Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing, China
| | - Yi Jiao
- Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing, China
| | - Mengxiao Zhang
- Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Honglin Liu
- Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China.
- China-Japan Friendship Hospital, Capital Medical University, Beijing, China.
| | - Haidong Tan
- Department of Hepatobiliary Surgery, China-Japan Friendship Hospital, Beijing, 100029, China.
| | - Cheng Xiao
- Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing, China.
- China-Japan Friendship Hospital, Capital Medical University, Beijing, China.
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An TY, Hu QM, Ni P, Hua YQ, Wang D, Duan GC, Chen SY, Jia B. N6-methyladenosine modification of hypoxia-inducible factor-1α regulates Helicobacter pylori-associated gastric cancer via the PI3K/AKT pathway. World J Gastrointest Oncol 2024; 16:3270-3283. [PMID: 39072157 PMCID: PMC11271789 DOI: 10.4251/wjgo.v16.i7.3270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 05/09/2024] [Accepted: 05/20/2024] [Indexed: 07/12/2024] Open
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.
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Affiliation(s)
- Tong-Yan An
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Quan-Man Hu
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Peng Ni
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Yan-Qiao Hua
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Di Wang
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Guang-Cai Duan
- Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - 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
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Wu S, Li C, Zhou H, Yang Y, Liang N, Fu Y, Luo Q, Zhan Y. The regulatory mechanism of m6A modification in gastric cancer. Discov Oncol 2024; 15:283. [PMID: 39009956 PMCID: PMC11250764 DOI: 10.1007/s12672-024-00994-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Accepted: 04/23/2024] [Indexed: 07/17/2024] Open
Abstract
To the best of our knowledge, N6-Methyladenosine (m6A) exerts a significant role in the occurrence and development of various tumors. Gastric cancer (GC), originating from the mucosal epithelium in the digestive tract, is the fifth most common cancer and the third most common cause of cancer death around the world. Therefore, it is urgent to explore the specific mechanism of tumorigenesis of GC. As we all know, m6A modification as the most common RNA modification, is involved in the modification of mRNA and ncRNA at the post-transcriptional level, which played a regulatory role in various biological processes. As identified by numerous studies, the m6A modification are able to influence the proliferation, apoptosis, migration, and invasion of GC. What's more, m6A modification are associated with EMT, drug resistance, and aerobic glycolysis in GC. m6A related-ncRNAs may be a valuable biomarker used by the prediction of GC diagnosis in the future. This review summarizes the role of m6A modification in the mechanism of gastric cancer, with the aim of identifying biological progress.
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Affiliation(s)
- Si Wu
- Department of Pathology, The First Affiliated Hospital of Zunyi Medical University, No. 149 Dalian Street, Huichuan District, Zunyi, 563000, Guizhou, China
| | - Chunming Li
- Department of Pathology, The First Affiliated Hospital of Zunyi Medical University, No. 149 Dalian Street, Huichuan District, Zunyi, 563000, Guizhou, China.
| | - Hanghao Zhou
- Department of Pathology, The First Affiliated Hospital of Zunyi Medical University, No. 149 Dalian Street, Huichuan District, Zunyi, 563000, Guizhou, China
| | - Ying Yang
- Department of Dermatology, The Second Affiliated Hospital of Zunyi Medical University, Intersection of Xinpu Street and Xinlong Street, Xinpu New District, Zunyi, 563000, Guizhou, China
| | - Na Liang
- Department of Histology and Embryology, Zunyi Medical University, No. 6 Xuefu West Street, Xinpu New District, Zunyi, Guizhou, China
| | - Yue Fu
- Department of Histology and Embryology, Zunyi Medical University, No. 6 Xuefu West Street, Xinpu New District, Zunyi, Guizhou, China
| | - Qingqing Luo
- Department of Physiology, Zunyi Medical University, No. 6 Xuefu West Street, Xinpu New District, Zunyi, Guizhou, China
| | - YaLi Zhan
- Department of Pathology, The First Affiliated Hospital of Zunyi Medical University, No. 149 Dalian Street, Huichuan District, Zunyi, 563000, Guizhou, China
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13
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Wang J, Yin H, Li G, Wu D, Xu Y, Chen Y, Wang X, Xing Y, Zhang T, Fei D, Yang P, Fang F, Tao Y, Li X, Yu J, Yang Y, Li Z, Shi L, Zhang Z, Pan J. METTL14 promotes neuroblastoma formation by inhibiting YWHAH via an m6A-YTHDF1-dependent mechanism. Cell Death Discov 2024; 10:186. [PMID: 38649363 PMCID: PMC11035551 DOI: 10.1038/s41420-024-01959-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 03/31/2024] [Accepted: 04/11/2024] [Indexed: 04/25/2024] Open
Abstract
Neuroblastoma (NB) is a common childhood tumor with a high incidence worldwide. The regulatory role of RNA N6-methyladenosine (m6A) in gene expression has attracted significant attention, and the impact of methyltransferase-like 14 (METTL14) on tumor progression has been extensively studied in various types of cancer. However, the specific influence of METTL14 on NB remains unexplored. Using data from the Target database, our study revealed significant upregulation of METTL14 expression in high-risk NB patients, with strong correlation with poor prognosis. Furthermore, we identified ETS1 and YY1 as upstream regulators that control the expression of METTL14. In vitro experiments involving the knockdown of METTL14 in NB cells demonstrated significant inhibition of cell proliferation, migration, and invasion. In addition, suppressing METTL14 inhibited NB tumorigenesis in nude mouse models. Through MeRIP-seq and RNA-seq analyses, we further discovered that YWHAH is a downstream target gene of METTL14. Mechanistically, we observed that methylated YWHAH transcripts, particularly those in the 5' UTR, were specifically recognized by the m6A "reader" protein YTHDF1, leading to the degradation of YWHAH mRNA. Moreover, the downregulation of YWHAH expression activated the PI3K/AKT signaling pathway, promoting NB cell activity. Overall, our study provides valuable insights into the oncogenic effects of METTL14 in NB cells, highlighting its role in inhibiting YWHAH expression through an m6A-YTHDF1-dependent mechanism. These findings also suggest the potential utility of a biomarker panel for prognostic prediction in NB patients.
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Affiliation(s)
- Jianwei Wang
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Hongli Yin
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Gen Li
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Di Wu
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Yunyun Xu
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Yanling Chen
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Xiaodong Wang
- Children's Hospital of Soochow University, Suzhou, China
| | - Yujiao Xing
- Children's Hospital of Soochow University, Suzhou, China
| | - Ting Zhang
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, China
| | - Danhong Fei
- Department of Pediatrics, Municipal Hospital Affiliated to Taizhou University, Taizhou, China
| | - Pengcheng Yang
- Department of Pediatric Surgery, The Affiliated Hospital of Yangzhou University, Yangzhou, China
| | - Fang Fang
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Yanfang Tao
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Xiaolu Li
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Juanjuan Yu
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Yang Yang
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Zhiheng Li
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China
| | - Lei Shi
- Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China
| | - Zimu Zhang
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China.
| | - Jian Pan
- Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China.
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14
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Wang Y, Ren H. Multi-omics sequencing revealed endostar combined with cisplatin treated non small cell lung cancer via anti-angiogenesis. BMC Cancer 2024; 24:187. [PMID: 38331776 PMCID: PMC10854066 DOI: 10.1186/s12885-023-11665-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 11/21/2023] [Indexed: 02/10/2024] Open
Abstract
BACKGROUND Endostar, an anti-angiogenic drug, has been approved for treating non-small cell lung cancer (NSCLC). At present, endostar combined with radiotherapy or chemotherapy has achieved ideal results in the treatment of some tumors, but there is a lack of application and study in NSCLC. This study investigated the therapeutic effect and potential mechanism of endostar combined with cisplatin (EC) in NSCLC. METHODS HE staining, TUNEL staining, immunofluorescence, colony formation ability, and cell migration ability were used to evaluate the anti-tumor activity of EC. The expressions of FMOD, VEGF, FGF-2, and PDGF-B were detected by western blotting and qPCR. The target of combination therapy was analyzed by m6A sequencing and RNA sequencing. METTL3 knockdown and overexpressed A549 cells were constructed and co-cultured with HUVECs to further evaluate the effect of METLL3 on combination therapy. RESULTS Combination therapy significantly reduced the colony formation and migration ability of NSCLC cells, induced cell apoptosis, and inhibited the tube formation ability of HUVECs. The results of m6A sequencing and RNA sequencing showed that the EC could down-regulate the expression level of FMOD in tumor tissues, which might be related to the reduction of its m6A methylation modification regulatory enzyme METTL3. Restricting FMOD expression could reduce the expression of FGF2, TGF-β1, VEGF and PDGF-B. Moreover, overexpression of METTLE almost abolished the anti-tumor effect of EC and promoted angiogenesis. CONCLUSIONS Endostar combined with cisplatin might exert anti-tumor effects by down-regulating the expression of METTL3 and FMOD.
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Affiliation(s)
- Yufei Wang
- Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road, 710061, Shanxi, Xi'an, Shanxi, P.R. China
- Department of Thoracic Surgery, The Affiliated Hospital of Inner Mongolia Medical University, 010050, Hohhot, Inner Mongolia, P.R. China
| | - Hong Ren
- Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road, 710061, Shanxi, Xi'an, Shanxi, P.R. China.
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15
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Rogers JD, Leusch FD, Chambers B, Daniels KD, Everett LJ, Judson R, Maruya K, Mehinto AC, Neale PA, Paul-Friedman K, Thomas R, Snyder SA, Harrill J. High-Throughput Transcriptomics of Water Extracts Detects Reductions in Biological Activity with Water Treatment Processes. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2024; 58:2027-2037. [PMID: 38235672 PMCID: PMC11003563 DOI: 10.1021/acs.est.3c07525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2024]
Abstract
The presence of numerous chemical contaminants from industrial, agricultural, and pharmaceutical sources in water supplies poses a potential risk to human and ecological health. Current chemical analyses suffer from limitations, including chemical coverage and high cost, and broad-coverage in vitro assays such as transcriptomics may further improve water quality monitoring by assessing a large range of possible effects. Here, we used high-throughput transcriptomics to assess the activity induced by field-derived water extracts in MCF7 breast carcinoma cells. Wastewater and surface water extracts induced the largest changes in expression among cell proliferation-related genes and neurological, estrogenic, and antibiotic pathways, whereas drinking and reclaimed water extracts that underwent advanced treatment showed substantially reduced bioactivity on both gene and pathway levels. Importantly, reclaimed water extracts induced fewer changes in gene expression than laboratory blanks, which reinforces previous conclusions based on targeted assays and improves confidence in bioassay-based monitoring of water quality.
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Affiliation(s)
- Jesse D. Rogers
- Center for Computational Toxicology and Exposure, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA
- Oak Ridge Institute for Science and Education, Oak Ridge, TN 37831, USA
| | - Frederic D.L. Leusch
- Australian Rivers Institute, School of Environment and Science, Griffith University, Southport Qld 4222, Australia
| | - Bryant Chambers
- Center for Computational Toxicology and Exposure, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA
| | | | - Logan J. Everett
- Center for Computational Toxicology and Exposure, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA
| | - Richard Judson
- Center for Computational Toxicology and Exposure, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA
| | - Keith Maruya
- Southern California Coastal Water Research Project Authority, 3535 Harbor Boulevard, Suite 110, Costa Mesa, CA 92626, USA
| | - Alvine C. Mehinto
- Southern California Coastal Water Research Project Authority, 3535 Harbor Boulevard, Suite 110, Costa Mesa, CA 92626, USA
| | - Peta A. Neale
- Australian Rivers Institute, School of Environment and Science, Griffith University, Southport Qld 4222, Australia
| | - Katie Paul-Friedman
- Center for Computational Toxicology and Exposure, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA
| | - Russell Thomas
- Center for Computational Toxicology and Exposure, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA
| | - Shane A. Snyder
- Nanyang Environment & Water Research Institute (NEWRI), Nanyang Technological University, 1 Cleantech Loop, CleanTech One, #06-08, 637141, Singapore
| | - Joshua Harrill
- Center for Computational Toxicology and Exposure, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA
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16
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Zhu C, Wu Q, Xu Y, Ma J, Hu Y, Wang J, Gao Z, Da M. Prognostic significance of N6-methyladenosine-modified related chemotransferase METTL3 in gastric carcinoma: Evidence from meta-analysis. Int J Biol Markers 2023; 38:185-193. [PMID: 37394831 DOI: 10.1177/03936155231184908] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
BACKGROUND N6-methyladenosine (m6A) methylation is known as the research hotspot for tumor epimodification, and its associated methyltransferase-like3 (METTL3) is significantly differentially expressed in gastric carcinoma, but its clinical value has not been summarized. This meta-analysis aimed to evaluate the prognostic significance of METTL3 in gastric carcinoma. MATERIAL AND METHODS Databases, including PubMed, EMBASE (Ovid platform), Science Direct, Scopus, MEDLINE, Google Scholar, Web of Science, and Cochrane Library, were used to identify relevant eligible studies. The endpoints included overall survival, progression-free survival, recurrence-free survival, post-progression survival, and disease-free survival. Hazard ratios (HR) with 95% confidence intervals (CI) were used to correlate METTL3 expression with prognosis. Subgroup and sensitivity analyses were performed. RESULTS Seven eligible studies involving 3034 gastric carcinoma patients were recruited for this meta-analysis. The analysis showed that high METTL3 expression was associated with significantly poorer overall survival (HR = 2.37, 95% CI 1.66-3.39, P < 0.01) and unfavorable disease-free survival (HR = 2.58, 95% CI 1.97-3.38, P < 0.01), as did unfavorable progression-free survival (HR = 1.48, 95% CI 1.19-1.84, P < 0.01)/recurrence-free survival (HR = 2.62, 95% CI 1.93-5.62, P < 0.01)/post-progression survival (HR = 1.53, 95% CI 1.22-1.91, P < 0.01). Subgroup analysis found that high METTL3 expression was associated with worse overall survival in patients with Chinese (HR = 2.21, 95% CI 1.48-3.29, P < 0.01), in studies with sample source from formalin-fixed, paraffin-embedded tissues (HR = 2.66, 95% CI 1.79-3.94, P < 0.01), and the reported directly from articles group (HR = 2.42, 95% CI 1.66-3.53, P < 0.01). The subgroup analysis that was performed based on sample size, detected method, and follow-up showed the same results. CONCLUSIONS High expression of METTL3 predicts poor prognosis in gastric carcinoma, indicating promise for METTL3 as a prognostic biomarker.Systematic review registration: https://www.crd.york.ac.uk/prospero, ID = CRD42023408519.
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Affiliation(s)
- Chenglou Zhu
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Qiong Wu
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Yan Xu
- The First School of Clinical Medicine, Gansu University of Chinese Medicine, Lanzhou, China
| | - Jichun Ma
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Yongli Hu
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Junhong Wang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Zhenhua Gao
- Hepatobiliary Surgery, The First People's Hospital of Baiyin, Baiyin, China
| | - Mingxu Da
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Department of Surgical Oncology, Gansu Provincial Hospital, Lanzhou, China
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Sun S, Cai X, Shao J, Zhang G, Liu S, Wang H. Machine learning-based approach for efficient prediction of diagnosis, prognosis and lymph node metastasis of papillary thyroid carcinoma using adhesion signature selection. MATHEMATICAL BIOSCIENCES AND ENGINEERING : MBE 2023; 20:20599-20623. [PMID: 38124567 DOI: 10.3934/mbe.2023911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2023]
Abstract
The association between adhesion function and papillary thyroid carcinoma (PTC) is increasingly recognized; however, the precise role of adhesion function in the pathogenesis and prognosis of PTC remains unclear. In this study, we employed the robust rank aggregation algorithm to identify 64 stable adhesion-related differentially expressed genes (ARDGs). Subsequently, using univariate Cox regression analysis, we identified 16 prognostic ARDGs. To construct PTC survival risk scoring models, we employed Lasso Cox and multivariate + stepwise Cox regression methods. Comparative analysis of these models revealed that the Lasso Cox regression model (LPSRSM) displayed superior performance. Further analyses identified age and LPSRSM as independent prognostic factors for PTC. Notably, patients classified as low-risk by LPSRSM exhibited significantly better prognosis, as demonstrated by Kaplan-Meier survival analyses. Additionally, we investigated the potential impact of adhesion feature on energy metabolism and inflammatory responses. Furthermore, leveraging the CMAP database, we screened 10 drugs that may improve prognosis. Finally, using Lasso regression analysis, we identified four genes for a diagnostic model of lymph node metastasis and three genes for a diagnostic model of tumor. These gene models hold promise for prognosis and disease diagnosis in PTC.
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Affiliation(s)
- Shuo Sun
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Beihua University, Beihua University, Jilin 132013, China
| | - Xiaoni Cai
- Department of General Surgery, Shangyu People's Hospital of Shaoxing, the Second Affiliated Hospital of Zhejiang University Medical College Hospital, Shaoxing 312399, China
| | - Jinhai Shao
- Department of General Surgery, Shangyu People's Hospital of Shaoxing, the Second Affiliated Hospital of Zhejiang University Medical College Hospital, Shaoxing 312399, China
| | - Guimei Zhang
- Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Jilin University, Changchun 130061, China
| | - Shan Liu
- Department of Nuclear Medicine, The Second Hospital of Jilin University, Jilin University, Changchun 130041, China
| | - Hongsheng Wang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Beihua University, Beihua University, Jilin 132013, China
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Hu J, Lin H, Wang C, Su Q, Cao B. METTL14‑mediated RNA methylation in digestive system tumors. Int J Mol Med 2023; 52:86. [PMID: 37539726 PMCID: PMC10555478 DOI: 10.3892/ijmm.2023.5289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 07/06/2023] [Indexed: 08/05/2023] Open
Abstract
N6‑methyladenosine (m6A) RNA methylation is one of the most common post‑transcriptional modification mechanism in eukaryotes. m6A is involved in almost all stages of the mRNA life cycle, specifically regulating its stability, splicing, export and translation. Methyltransferase‑like 14 (METTL14) is a particularly important m6A methylation 'writer' that can recognize RNA substrates. METTL14 has been documented to improve the activity and catalytic efficiency of METTL3. However, as individual proteins they can also regulate different biological processes. Malignancies in the digestive system are some of the most common malignancies found in humans, which are typically associated with poor prognoses with limited clinical solutions. METTL14‑mediated methylation has been implicated in both the potentiation and inhibition of digestive system tumor growth, cell invasion and metastasis, in addition to drug resistance. In the present review, the research progress and regulatory mechanisms of METTL14‑mediated methylation in digestive system malignancies were summarized. In addition, future research directions and the potential for its clinical application were examined.
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Affiliation(s)
- Jiexuan Hu
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Haishan Lin
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Cong Wang
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Qiang Su
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Bangwei Cao
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
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19
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Ding SQ, Zhang XP, Pei JP, Bai X, Ma JJ, Zhang CD, Dai DQ. Role of N6-methyladenosine RNA modification in gastric cancer. Cell Death Discov 2023; 9:241. [PMID: 37443100 DOI: 10.1038/s41420-023-01485-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 06/02/2023] [Accepted: 06/14/2023] [Indexed: 07/15/2023] Open
Abstract
N6-methyladenosine (m6A) RNA methylation is the most prevalent internal modification of mammalian messenger RNA. The m6A modification affects multiple aspects of RNA metabolism, including processing, splicing, export, stability, and translation through the reversible regulation of methyltransferases (Writers), demethylases (Erasers), and recognition binding proteins (Readers). Accumulating evidence indicates that altered m6A levels are associated with a variety of human cancers. Recently, dysregulation of m6A methylation was shown to be involved in the occurrence and development of gastric cancer (GC) through various pathways. Thus, elucidating the relationship between m6A and the pathogenesis of GC has important clinical implications for the diagnosis, treatment, and prognosis of GC patients. In this review, we evaluate the potential role and clinical significance of m6A-related proteins which function in GC in an m6A-dependent manner. We discuss current issues regarding m6A-targeted inhibition of GC, explore new methods for GC diagnosis and prognosis, consider new targets for GC treatment, and provide a reasonable outlook for the future of GC research.
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Affiliation(s)
- Si-Qi Ding
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, 110032, Shenyang, China
| | - Xue-Ping Zhang
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, 110032, Shenyang, China
| | - Jun-Peng Pei
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, 110032, Shenyang, China
| | - Xiao Bai
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, 110032, Shenyang, China
| | - Jin-Jie Ma
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, 110032, Shenyang, China
| | - Chun-Dong Zhang
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, 110032, Shenyang, China
| | - Dong-Qiu Dai
- Department of Gastrointestinal Surgery, The Fourth Affiliated Hospital of China Medical University, 110032, Shenyang, China.
- Cancer Center, The Fourth Affiliated Hospital of China Medical University, 110032, Shenyang, China.
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METTL3 promotes glycolysis and cholangiocarcinoma progression by mediating the m6A modification of AKR1B10. Cancer Cell Int 2022; 22:385. [PMID: 36476503 PMCID: PMC9730622 DOI: 10.1186/s12935-022-02809-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 11/25/2022] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE N6-methyladenosine (m6A) RNA methylation is involved in governing the mechanism of tumor progression. We aimed to excavate the biological role and mechanism of the m6A methyltransferase METTL3 in cholangiocarcinoma (CCA). METHODS METTL3 expression was determined by database and tissue microarray analyses. The role of METTL3 in CCA was explored by loss- and gain-of-function experiments. The m6A target of METTL3 was detected by RNA sequencing. The role of AKR1B10 in CCA was explored, and the association between METTL3 and AKR1B10 was confirmed by rescue experiments. RESULT METTL3 expression was upregulated in CCA tissue, and higher METTL3 expression was implicated in poor prognoses in CCA patients. Overexpression of METTL3 facilitated proliferation, migration, invasion, glucose uptake, and lactate production in CCA cells, whereas knockdown of METTL3 had the opposite effects. We further found that METTL3 deficiency inhibited CCA tumor growth in vivo. RNA sequencing and MeRIP-qPCR confirmed that METTL3 enhanced AKR1B10 expression and m6A modification levels. Furthermore, METTL3 directly binds with AKR1B10 at an m6A modification site. A CCA tissue microarray showed that AKR1B10 expression was upregulated in CCA tissue and that silencing AKR1B10 suppressed the malignant phenotype mentioned above in CCA. Notably, knockdown of AKR1B10 rescued the tumor-promoting effects induced by METTL3 overexpression. CONCLUSION Elevated METTL3 expression promotes tumor growth and glycolysis in CCA through m6A modification of AKR1B10, indicating that METTL3 is a potential target for blocking glycolysis for application in CCA therapy.
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Zhang G, Wang T, Huang Z, Chen Y, Sun L, Xia X, He F, Fan C, Wang S, Liu W. METTL3 dual regulation of the stability of LINC00662 and VEGFA RNAs promotes colorectal cancer angiogenesis. Discov Oncol 2022; 13:89. [PMID: 36114893 PMCID: PMC9482670 DOI: 10.1007/s12672-022-00557-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 09/08/2022] [Indexed: 11/26/2022] Open
Abstract
PURPOSE The angiogenesis is among the primary factors that affect tumor recurrence and distant organ metastasis in colorectal cancer (CRC). N6-methyladenosine (m6A) modification is one of the most common chemical modifications in eukaryotic mRNA, especially at the post-transcriptional level. Methyltransferase-like 3 (METTL3) promoting angiogenesis in a variety of tumors has been reported. However, the mechanism of how METTL3 dual-regulates the stability of long non-coding RNAs (lncRNAs) and vascular-related factor RNAs to affect angiogenesis in CRC is unclear. METHODS 64 paired CRC and adjacent normal tissues were collected. In vitro, quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC), actinomycin assay, methylated RNA immunoprecipitation (MeRIP) experiment,3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT) and colony formation assay were performed. The functions were also studied in zebrafish model animals in vivo. RESULTS We found that the vascular endothelial growth factor A(VEGFA), METTL3 and LINC00662 RNAs were highly expressed in CRC, and that METTL3 was significantly positively correlated with LINC00662 and VEGFA. The protein expression levels of CD31, CD34, VEGFA, m6A and METTL3 were all significantly increased in the CRC tissues. The angiogenesis experiments both in vivo and in vitro found that METTL3 and LINC00662 promoted angiogenesis in CRC. The actinomycin assay indicated that METTL3 maintained the stability of LINC00662 and VEGFA RNAs. In addition, the MeRIP experiment confirmed that the LINC00662 and VEGFA RNAs had METTL3-enriched sites. CONCLUSION These findings suggest that METTL3 and LINC00662 may both serve as diagnostic and prognostic predictive biomarkers for CRC and potential targets for anti-vascular therapy.
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Affiliation(s)
- Guoying Zhang
- Department of General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, No. 68, Changle Road, Nanjing, 210006, Jiangsu, China
- Department of Clinical Laboratory, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Nanjing University of Traditional Chinese Medicine, No. 179, Xiaolingwei Street, Nanjing, 210014, Jiangsu, China
| | - Tianjun Wang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zihui Huang
- Department of Clinical Laboratory, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Nanjing University of Traditional Chinese Medicine, No. 179, Xiaolingwei Street, Nanjing, 210014, Jiangsu, China
| | - Yuanyuan Chen
- Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Li Sun
- Department of General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, No. 68, Changle Road, Nanjing, 210006, Jiangsu, China
| | - Xia Xia
- Department of Clinical Laboratory, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Nanjing University of Traditional Chinese Medicine, No. 179, Xiaolingwei Street, Nanjing, 210014, Jiangsu, China
| | - Fang He
- Department of Clinical Laboratory, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Nanjing University of Traditional Chinese Medicine, No. 179, Xiaolingwei Street, Nanjing, 210014, Jiangsu, China
| | - Chenying Fan
- Department of Clinical Laboratory, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Nanjing University of Traditional Chinese Medicine, No. 179, Xiaolingwei Street, Nanjing, 210014, Jiangsu, China
| | - Shukui Wang
- Department of General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, No. 68, Changle Road, Nanjing, 210006, Jiangsu, China.
- Jiangsu Collaborative Innovation Center on Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Wanli Liu
- Department of Clinical Laboratory, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Nanjing University of Traditional Chinese Medicine, No. 179, Xiaolingwei Street, Nanjing, 210014, Jiangsu, China.
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Xu Z, Chen Q, Shu L, Zhang C, Liu W, Wang P. Expression profiles of m6A RNA methylation regulators, PD-L1 and immune infiltrates in gastric cancer. Front Oncol 2022; 12:970367. [PMID: 36003776 PMCID: PMC9393729 DOI: 10.3389/fonc.2022.970367] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 06/30/2022] [Indexed: 12/01/2022] Open
Abstract
Gastric cancer is the fourth most frequent cancer and has a high death rate. Immunotherapy represented by PD-1 has brought hope for the treatment of advanced gastric cancer. Methylation of the m6A genes is linked to the onset and progression of numerous cancers, but there are few studies on gastric cancer. The main purpose of this study aims to analyze the relationship between m6A RNA methylation regulators, PD-L1, prognosis and tumor immune microenvironment (TIME) in gastric cancer. The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx) databases were used to acquire transcriptomic data and clinical information from gastric cancer patients. The changes in m6A regulator expression levels in gastric cancer tissues and normal tissues were studied. Consensus clustering analysis was used to separate gastric cancer samples into two categories. We employed Least Absolute Shrinkage, Selection Operator (LASSO) Cox regression analysis, Gene Set Enrichment Analysis (GSEA), and cBioPortal to analyze the m6A regulators, PD-L1 and TIME in gastric cancer. In gastric cancer tissues, the majority of m6A regulatory factors are considerably overexpressed. Two gastric cancer subgroups (Cluster1/2) based on consensus clustering of 21 m6A regulators. PD-L1 and PD-1 expression levels were significantly higher in gastric cancer tissues, and they were significantly linked with METTL3, WTAP, HNRNPD, ZC3H7B, METTL14, FTO, PCIF1, HNRNPC, YTHDF1 and YTDHF2. Cluster1 showed a large increase in resting memory CD4+ T cells, regulatory T cells, naïve B cells, active NK cells, and resting Mast cells. Cluster1 and Cluster2 were shown to be involved in numerous critical signaling pathways, including base excision repair, cell cycle, nucleotide excision repair, RNA degradation, and spliceosome pathways. Gastric cancer RiskScores based on prognostic factors have been found as independent prognostic indicators. The amount of tumor-infiltrating immune cells is dynamically affected by changes in the copy number of m6A methylation regulators associated with TIME.
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Affiliation(s)
- Zhiyuan Xu
- Department of Gastric Surgery, the Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institutes of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou, China
- *Correspondence: Zhiyuan Xu, ; Peter Wang,
| | - Qiuli Chen
- Department of Research and Development, Zhejiang Zhongwei Medical Research Center, Hangzhou, Zhejiang, China
| | - Lilu Shu
- Department of Research and Development, Zhejiang Zhongwei Medical Research Center, Hangzhou, Zhejiang, China
| | - Chunye Zhang
- National University of Singapore (Suzhou) Research Institute, Suzhou, China
| | - Wenjun Liu
- Department of Research and Development, Zhejiang Zhongwei Medical Research Center, Hangzhou, Zhejiang, China
| | - Peter Wang
- Department of Research and Development, Zhejiang Zhongwei Medical Research Center, Hangzhou, Zhejiang, China
- *Correspondence: Zhiyuan Xu, ; Peter Wang,
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