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Comprehensive analysis of the function of helicobacter-associated ferroptosis gene YWHAE in gastric cancer through multi-omics integration, molecular docking, and machine learning

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Abstract

Gastric cancer is strongly associated with Helicobacter pylori (H. pylori) infection. However, the molecular mechanisms underlying the development of gastric cancer in the context of H. pylori infection, particularly in relation to ferroptosis, remain poorly understood. In this study, we investigated the role of the Helicobacter-associated ferroptosis gene YWHAE in gastric cancer. We analyzed multi-omics data, performed molecular docking, and employed machine learning to comprehensively evaluate the expression, function, and potential implications in gastric cancer, including its influence on drug sensitivity, mutation, immune microenvironment, immunotherapy, and prognosis. Our findings demonstrated that the YWHAE gene exhibits high expression in both H. pylori-associated gastritis and gastric cancer. Pan-cancer analysis revealed elevated expression of YWHAE in several cancer types compared to normal tissues. We also examined the methylation, single nucleotide variations (SNVs), and copy number variations (CNVs) associated with YWHAE. Single-cell analysis indicated that the YWHAE gene is expressed in various cell types, with its expression level potentially influenced by H. pylori infection. Functionally, we observed a positive correlation between YWHAE gene expression and ferroptosis in gastric cancer and associated with multiple cancer-related signaling pathways, including MAPK, NF-κB, and PI3K. Furthermore, we predicted five small molecule compounds that show promise for treating gastric cancer patients and screened five drugs with the highest correlation with YWHAE and validated them by molecular docking. Additionally, significant differences were observed in various immune cell types and immunotherapeutic response between the high and low YWHAE gene expression groups. Moreover, we found a positive correlation between YWHAE gene expression and the tumour mutation burden (TMB). By applying 10 machine learning algorithms and 101 integration combinations, we developed a prognostic model for YWHAE-related genes. Finally, qRT-PCR and immunohistochemistry (IHC) consistently demonstrated the upregulation of YWHAE in gastric cancer. In conclusion, we conducted a comprehensive analysis of YWHAE gene in gastric cancer. Our findings provided novel insights into the role of YWHAE as a gene associated with H. pylori infection and ferroptosis in gastric cancer and expanded our understanding of the molecular mechanisms underlying gastric carcinogenesis.

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Data availability

The datasets of this article were generated from the TCGA database, GEO database and previous studies.

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Acknowledgements

We appreciate the Science and Technology Projects of Jiangxi Province and the TCGA database.

Funding

This research was funded by the National Natural Science Foundation of China (Grant Nos.82270593, 82200628).

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Authors and Affiliations

  1. Department of Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China

    Dingwei Liu, Jianxiang Peng, Jun Xie & Yong Xie

  2. Gastroenterology Institute of Jiangxi Province, Nanchang, Jiangxi, China

    Dingwei Liu, Jianxiang Peng, Jun Xie & Yong Xie

  3. Key Laboratory of Digestive Diseases of Jiangxi Province, Nanchang, Jiangxi, China

    Dingwei Liu, Jianxiang Peng, Jun Xie & Yong Xie

  4. Jiangxi Clinical Research Center for Gastroenterology, Nanchang, China

    Dingwei Liu, Jianxiang Peng, Jun Xie & Yong Xie

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Contributions

YX designed the study. DL performed data analysis, graphing and writing. JP and JX helped modify the article and supervise the study. All authors read and approved the final manuscript.

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Correspondence to Yong Xie.

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The study was approved by The First Affiliated Hospital of Nanchang University Ethics Committee on Medical Research.

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Liu, D., Peng, J., Xie, J. et al. Comprehensive analysis of the function of helicobacter-associated ferroptosis gene YWHAE in gastric cancer through multi-omics integration, molecular docking, and machine learning. Apoptosis 29, 439–456 (2024). https://doi.org/10.1007/s10495-023-01916-3

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