山东大学耳鼻喉眼学报 ›› 2020, Vol. 34 ›› Issue (4): 117-124.doi: 10.6040/j.issn.1673-3770.0.2020.189

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西妥昔单抗治疗头颈部鳞状细胞癌差异表达基因的生物信息学分析

于克娜1,孙凯月2,张杰1,金鹏1   

  1. 于克娜1, 孙凯月2, 张杰1, 金鹏11. 山东大学第二医院 耳鼻咽喉头颈外科, 山东 济南 250033;
    2. 山东大学附属山东省耳鼻喉医院, 山东 济南 250022
  • 收稿日期:2020-04-26 出版日期:2020-07-20 发布日期:2020-08-28
  • 基金资助:
    国家自然科学基金委青年科学基金项目(81800885);山东省自然科学基金(ZR2018PH021)

Analysis of differentially expressed genes during cetuximab treatment of head and neck squamous cell carcinoma using bioinformaticsYU Kena1, SUN Kaiyue2, ZHANG Jie1, JIN Peng1 1. Department of Otorhinolaryngology & Head and Neck Surgery, The Second Hospital of Shandong University, Jinan 250033, Shandong, China; 2. Shandong Provincial Otorhinolaryngology Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250022, Shandong, ChinaAbstract:

ObjectiveThe aim of this study was to provide new perspectives and targets for the treatment of HNSCC by screening differentially expressed genes during cetuximab treatment of head and neck squamous cell carcinoma(HNSCC)using bioinformatics. MethodsThe chip dataset, GSE109756, was downloaded from the GEO database, and the online analysis tool, GEO2R, was used to screen differentially expressed genes in head and neck squamous cell carcinoma tissues treated with and without cetuximab. The DAVID 6.8 and STRING online software were used to analyze the function of the differentially expressed genes, their pathway enrichment, and their protein interactions. Cytoscape was used to visualize and analyze the protein interactions. The online analysis tool, X2K, was used to find the transcription factors, the kinases of differentially expressed genes, and their mutual regulatory relationship with the targeted genes. ResultsNinety-one differentially expressed genes, including 50 up-regulated and 41 down-regulated genes(P<0.05; | logFC | > 1), were found in head and neck squamous cell carcinoma tissues treated with and without cetuximab. The GO and KEGG pathway analyses suggested that these differentially expressed genes were mainly enriched with immunomodulation, extracellular matrix, and other processes. Through the construction of a protein-protein interaction network, we screened CD163, VSIG4, and 3 other core differentially expressed genes(P<0.05), which were up-regulated after cetuximab treatment. In addition, our analysis shows that transcription factors, including SUZ12, TP63, and ESR1, played a key role in cetuximab treatment(P<0.05)and MAPK14, CDK1, and MAPK1 were the most important kinases during the process(P<0.05). ConclusionCD163, VSIG4, and the aforementioned transcription factors and protein kinases may be involved in the biological processes that underlie cetuximab treatment of HNSCC. This study provides new perspectives to facilitate further understanding of the biological mechanism that underlies cetuximab treatment of HNSCC and the exploration of the effectiveness of HNSCC treatment.   

  1. Key words: Head and neck squamous cell carcinoma;
    Bioinformatics analysis;
    cetuximab;
    Differentially expressed genes头颈部鳞状细胞癌(head and neck squamous cell carcinoma, HNSCC)约占头颈部恶性肿瘤的95%, 多发生在口咽、下咽或口腔, 其发病率具有上升的趋势, 且预后较差［1］。如在喉癌中, 除声门型喉癌, 声门上型及声门下型患者的早期症状通常较为隐蔽, 半数以上患者就诊时即处于中晚期。尽管HNSCC的手术和综合治疗手段近年来取得了较大进展, 早期淋巴结转移和侵袭性生长等恶性病理特征仍是其术后复发及转移率高、生存率低和远期疗效差的重要因素［2］。复发性和转移性HNSCC患者的生活质量差, 通常无法进行手术治疗, 且放化疗治疗欠敏感。近年来, 肿瘤治疗的靶向类药物开始逐步应用于临床, 如上皮生长因子受体(epidermal growth factor receptor, EGFR)和血管内皮生长因子(vascular endothelial growth factor, VEGF)等。其中EGFR 特异性单克隆抗体——西妥昔单抗的问世, 为HNSCC尤其是其复发或转移性患者的有效治疗提供了可能, 但部分患者靶向药物治疗后可能出现耐药性, 从而失去继续治疗的机会［3］。HNSCC的发生、发展和疾病转归是复杂的多因素生物学过程。因此, 对西妥昔单抗靶向药物治疗中的关键基因、基因间的相互作用及调节进行探索与分析, 可能为深入理解西妥昔单抗治疗HNSCC的生物学机制、解决西妥昔单抗的耐药性问题开辟新的切入点, 从而为头颈部鳞状细胞癌的治疗提供新的思路和靶点。
  • Received:2020-04-26 Online:2020-07-20 Published:2020-08-28

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摘要： 目的 通过生物信息学技术筛选西妥昔单抗治疗头颈部鳞状细胞癌(HNSCC)的差异表达基因,为头颈部鳞状细胞癌的治疗提供新的思路和靶点。 方法 从GEO数据库下载芯片数据集GSE109756,使用在线分析工具GEO2R筛选使用和未使用西妥昔单抗治疗的头颈部鳞状细胞癌组织间的差异表达基因,通过DAVID 6.8 和STRING在线软件分析差异表达基因的功能、通路富集分析和蛋白相互作用分析,Cytoscape对蛋白相互作用进行可视化和模块分析,在线分析工具X2K分析差异表达基因的转录因子、激酶并分析它们与靶基因之间的相互调控关系。 结果 研究发现经西妥昔单抗治疗的头颈部鳞状细胞癌组织与未使用其治疗的组织间共有91个差异表达基因,其中上调基因50个,下调基因41个(P<0.05,| logFC |>1)。GO分析和KEGG通路分析显示,这些差异表达的基因主要富集在免疫调节、细胞外基质等生物过程。通过蛋白-蛋白相互作用网络的构建,筛选出CD163和VSIG4等核心差异表达基因(P<0.05),它们均在西妥昔单抗治疗后表达上调。此外,分析显示西妥昔单抗治疗过程中发挥关键作用的转录因子包括SUZ12、TP63、ESR1等(P<0.05),而MAPK14、CDK1、MAPK1等是这一治疗过程中最重要的激酶(P<0.05)。结论〓CD163、VSIG4及上述转录因子、蛋白激酶可能参与了西妥昔单抗治疗HNSCC的生物过程,研究为进一步深入理解西妥昔单抗治疗HNSCC的生物学机制、探索HNSCC治疗的有效方案提供了新思路。

关键词: 头颈部鳞状细胞癌, 生物信息学分析, 西妥昔单抗, 差异表达基因

Abstract: Objective The aim of this study was to provide new perspectives and targets for the treatment of HNSCC by screening differentially expressed genes during cetuximab treatment of head and neck squamous cell carcinoma(HNSCC)using bioinformatics. Methods The chip dataset, GSE109756, was downloaded from the GEO database, and the online analysis tool, GEO2R, was used to screen differentially expressed genes in head and neck squamous cell carcinoma tissues treated with and without cetuximab. The DAVID 6.8 and STRING online software were used to analyze the function of the differentially expressed genes, their pathway enrichment, and their protein interactions. Cytoscape was used to visualize and analyze the protein interactions. The online analysis tool, X2K, was used to find the transcription factors, the kinases of differentially expressed genes, and their mutual regulatory relationship with the targeted genes. Results Ninety-one differentially expressed genes, including 50 up-regulated and 41 down-regulated genes(P<0.05; | logFC | > 1), were found in head and neck squamous cell carcinoma tissues treated with and without cetuximab. The GO and KEGG pathway analyses suggested that these differentially expressed genes were mainly enriched with immunomodulation, extracellular matrix, and other processes. Through the construction of a protein-protein interaction network, we screened CD163, VSIG4, and 3 other core differentially expressed genes(P<0.05), which were up-regulated after cetuximab treatment. In addition, our analysis shows that transcription factors, including SUZ12, TP63, and ESR1, played a key role in cetuximab treatment(P<0.05)and MAPK14, CDK1, and MAPK1 were the most important kinases during the process(P<0.05). Conclusion CD163, VSIG4, and the aforementioned transcription factors and protein kinases may be involved in the biological processes that underlie cetuximab treatment of HNSCC. This study provides new perspectives to facilitate further understanding of the biological mechanism that underlies cetuximab treatment of HNSCC and the exploration of the effectiveness of HNSCC treatment.

Key words: Head and neck squamous cell carcinoma, Bioinformatics analysis, cetuximab, Differentially expressed genes

中图分类号: 

  • R739.6
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