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Identification of differentially expressed genes and signaling pathways using bioinformatics in interstitial lung disease due to tyrosine kinase inhibitors targeting the epidermal growth factor receptor

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Summary

Interstitial lung disease (ILD) is a rare but lethal adverse effect of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) treatment. The specific mechanism of this disease is not fully understood. To systematically analyze genes associated with EGFR-TKI induced ILD, gene data of EGFR-TKI induced ILD were extracted initially using text mining, and then the intersection between genes from text mining and Gene Expression Omnibus (GEO) dataset was taken for further protein-protein interaction (PPI) analysis using String-bd database. Go ontology (GO) and pathway enrichment analysis was also conducted based on Database of Annotation, Visualization and Integrated Discovery (DAVID) platform. The PPI network generated by STRING was visualized by Cytoscape, and the topology scores, functional regions and gene annotations were analyzed using plugins of CytoNCA, molecular complex detection (MCODE) and ClueGo. 37 genes were identified as EGFR-TKI induced ILD related. Gene enrichment analysis yield 18 enriched GO terms and 12 associated pathways. A PPI network that included 199 interactions for a total of 35 genes was constructed. Ten genes were selected as hub genes using CytoNCA plugin, and four highly connected clusters were identified using MCODE plugin. GO and pathway annotation analysis for the cluster one revealed that five genes were associated with either response to dexamethasone or with lung fibrosis, including CTGF, CCL2, IGF1, EGFR and ICAM1. Our data might be useful to reveal the pathological mechanisms of EGFR-TKI induced ILD and provide evidence for the diagnosis and treatment in the future.

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Author notes

  1. Yuan Lu and Ang Li contributed equally to this work.

Authors and Affiliations

  1. Department of Respiratory, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Xueyuan AVE 1098, Xili University Town, Shenzhen, 518055, Guangdong, People’s Republic of China

    Yuan Lu, Lihong Zhang, Zhicheng Zhong, Wen Zhao, Ping Tang & Xinling Ren

  2. The State Key Laboratory of Cancer Biology, Department of Immunology, Air Force Military Medical University (Fourth Military Medical University), 169 Changle West Road, Xi’an, 710032, People’s Republic of China

    Ang Li

  3. Department of Clinical Genetics and Experimental Medicine, Fuzhou General Hospital, Xiamen University School of Medicine, Fuzhou, Fujian, 350025, People’s Republic of China

    Xiaofeng Lai

  4. Department of Respiratory, Xijing Hospital, Air Force Military Medical University (Fourth Military Medical University), Changle, West Road 127, Xi’an, 710032, People’s Republic of China

    Jun Jiang

  5. Department of Urology, Fuzhou Dongfang Hospital, Xiamen University, Xierhuan Northern Road 156, Fuzhou, 350025, People’s Republic of China

    Hu Zhao

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  1. Yuan Lu
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  2. Ang Li
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  3. Xiaofeng Lai
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  4. Jun Jiang
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  5. Lihong Zhang
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  6. Zhicheng Zhong
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  7. Wen Zhao
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  8. Ping Tang
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  9. Hu Zhao
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  10. Xinling Ren
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Contributions

Yuan Lu, Ang Li, Hu Zhao and Xinling Ren conceived and designed the study. Yuan Lu and Ang Li were responsible for the collection, analysis and interpretation of the data. Yuan Lu, Wen Zhao and Ping Tang were responsible for data visualization. Yuan Lu, Ang Li, XiaoFeng Lai drafted the manuscript, and all authors critically revised it for important intellectual content. Xinling Ren obtained funding, and Hu Zhao was responsible for logistic support. All authors had final approval of the submitted manuscript.

Corresponding authors

Correspondence to Hu Zhao or Xinling Ren.

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Funding

This study was funded by National Natural Science Foundation of China (No. 81871880), and Director Fund of Shenzhen University General Hospital (No. 0000040546).

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All authors have no conflict of interest.

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This article does not contain any studies with human participants performed by any of the authors.

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Lu, Y., Li, A., Lai, X. et al. Identification of differentially expressed genes and signaling pathways using bioinformatics in interstitial lung disease due to tyrosine kinase inhibitors targeting the epidermal growth factor receptor. Invest New Drugs 37, 384–400 (2019). https://doi.org/10.1007/s10637-018-0664-z

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