Journal of Otolaryngology and Ophthalmology of Shandong University ›› 2020, Vol. 34 ›› Issue (4): 117-124.doi: 10.6040/j.issn.1673-3770.0.2020.189

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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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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

CLC Number: 

  • R739.6
[1] 李国俊, 潘新良, 雷大鹏, 等. 口咽部鳞状细胞癌与性行为和人乳头状瘤病毒感染[J]. 山东大学耳鼻喉眼学报, 2013, 27(1): 1-7. doi: 10.6040/j.issn.1673-3770.1.2012.015. LI Guojun, PAN Xinliang, LEI Dapeng, et al. Sexual behavior and HPV infection in squamous cell carcinoma of the oropharynx[J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2013, 27(1): 1-7. doi: 10.6040/j.issn.1673-3770.1.2012.015.
[2] Zhang SY, Lu ZM, Luo XN, et al. Retrospective analysis of prognostic factors in 205 patients with laryngeal squamous cell carcinoma who underwent surgical treatment[J]. PLoS One, 2013, 8(4): e60157. doi: 10.1371/journal.pone.0060157.
[3] 吴静, 刘业海. 头颈部鳞状细胞癌的靶向治疗研究进展[J]. 山东大学耳鼻喉眼学报, 2018, 32(5): 97-102. doi: 10.6040/j.issn.1673-3770.0.2018.058. WU Jing, LIU Yehai. Targeted therapy for head and neck squamous cell carcinoma[J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2018, 32(5): 97-102. doi: 10.6040/j.issn.1673-3770.0.2018.058.
[4] 廖秀萍, 吕念, 龙森兰. 喉鳞状细胞癌中IL-18的表达与临床病理的关系及西妥昔单抗对其表达的影响[J]. 海南医学院学报, 2015, 21(10): 1361-1364. doi:10.13210/j.cnki.jhmu.20150422.017. LIAO Xiuping, LV Nian, LONG senlan. Relationship between interleukin 18 expression in laryngeal squamous cell carcinoma and clinical pathology as well as the effect of cetuximab on its expression[J]. Journal of Hainan Medical University, 2015, 21(10): 1361-1364. doi:10.13210/j.cnki.jhmu.20150422.017.
[5] Geiger B, Yamada KM. Molecular architecture and function of matrix adhesions[J]. Cold Spring Harb Perspect Biol, 2011, 3(5): a005033. doi: 10.1101/cshperspect.a005033.
[6] 丁婷婷, 泮红飞, 张红, 等. M2型巨噬细胞标志物CD163与肿瘤的研究进展[J]. 中国免疫学杂志, 2018, 34(7): 1114-1117. doi: 10.3969/j.issn.1000-484X.2018.07.030. DING Tingting, PAN Hongfei, ZHANG Hong,et al.Research progress of M2 macrophage marker CD163 and tumor[J]. Chinese Journal of Immunology, 2018, 34(7): 1114-1117. doi: 10.3969/j.issn.1000-484X.2018.07.030.
[7] 金美花, 陈永文, 李春实. 新型免疫调节分子VSIG4介导免疫清除及炎症的研究进展[J]. 免疫学杂志, 2014, 30(12): 1108-1112. doi: 10.13431/j.cnki.immunol.j.20140245. JIN Meihua, CHEN Yongwen, LI Chunshi. VSIG4: a novel immunoregulation molecular mediating immune clearance and inflammation[J]. Immunological Journal, 2014, 30(12): 1108-1112. doi: 10.13431/j.cnki.immunol.j.20140245..
[8] 朱利红, 段树鹏, 秦海霞, 等. miR-198靶向MAPK1调控宫颈癌HeLa细胞增殖、凋亡和侵袭[J]. 肿瘤防治研究, 2018, 45(12): 959-964. doi: 10.13431/j.cnki.immunol.j.20140245. ZHU Lihong, DUAN Shupeng, QIN Haixia, et al. MiR-198 targets MAPK1 to regulate proliferation, apoptosis and invasion of cervical cancer HeLa cells[J]. Cancer Research on Prevention and Treatment, 2018, 45(12): 959-964. doi: 10.13431/j.cnki.immunol.j.20140245.
[9] Reyes-Gibby CC, Wang J, Silvas MR, et al. MAPK1/ERK2 as novel target genes for pain in head and neck cancer patients[J]. BMC Genet, 2016, 17: 40. doi: 10.1186/s12863-016-0348-7.
[10] Wen YH, Li H, Zeng Y, et al. MAPK1E322K mutation increases head and neck squamous cell carcinoma sensitivity to erlotinib through enhanced secretion of amphiregulin[J]. Oncotarget, 2016, 7(17): 23300-23311. doi: 10.18632/oncotarget.8188.
[11] Mesquita FP, Moreira-Nunes CA, da Silva EL, et al. MAPK14(p38α)inhibition effects against metastatic gastric cancer cells: a potential biomarker and pharmacological target[J]. Toxicol In Vitro, 2020, 66: 104839. doi: 10.1016/j.tiv.2020.104839.
[12] Sahu V, Nigam L, Agnihotri V, et al. Diagnostic significance of p38 isoforms(p38α, p38β, p38γ, p38δ)in head and neck squamous cell carcinoma: comparative serum level evaluation and design of novel peptide inhibitor targeting the same[J]. Cancer Res Treat, 2019, 51(1): 313-325. doi: 10.4143/crt.2018.105.
[13] 李丽, 李雪婷, 张振华, 等. 食管癌变过程中CyclinB1、CDK1及细胞周期调控因子p53、Rb的表达及意义[J]. 世界华人消化杂志, 2015, 23(31): 4968-4974. doi: 10.1007/s13277-016-4991-4. LI Li, LI Xueting, ZHANG Zhenhua, et al. Significance of expression of CyclinB1, CDK1, p53, and Rb in esophageal oncogenesis[J]. World Chinese Journal of Digestology, 2015, 23(31): 4968-4974. doi: 10.1007/s13277-016-4991-4.
[14] Bednarek K, Kiwerska K, Szaumkessel M, et al. Recurrent CDK1 overexpression in laryngeal squamous cell carcinoma[J]. Tumor Biol, 2016, 37(8): 11115-11126. doi: 10.1007/s13277-016-4991-4.
[15] Przybyl J, Kidzinski L, Hastie T, et al. Gene expression profiling of low-grade endometrial stromal sarcoma indicates fusion protein-mediated activation of the Wnt signaling pathway[J]. Gynecol Oncol, 2018, 149(2): 388-393. doi: 10.1016/j.ygyno.2018.03.007.
[16] Xue CL, Wang KY, Jiang XF, et al. The down-regulation of SUZ12 accelerates the migration and invasion of liver cancer cells via activating ERK1/2 pathway[J]. J Cancer, 2019, 10(6): 1375-1384. doi: 10.7150/jca.29932.
[17] Su SK, Li CY, Lei PJ, et al. The EZH1-SUZ12 complex positively regulates the transcription of NF-κB target genes through interaction with UXT[J]. J Cell Sci, 2016, 129(12): 2343-2353. doi: 10.1242/jcs.185546.
[18] Broux M, Prieto C, Demeyer S, et al. Suz12 inactivation cooperates with JAK3 mutant signaling in the development of T-cell acute lymphoblastic leukemia[J]. Blood, 2019, 134(16): 1323-1336. doi: 10.1182/blood.2019000015.
[19] Malsin ES, Kim S, Lam AP, et al. Macrophages as a source and recipient of wnt signals[J]. Front Immunol, 2019, 10: 1813. doi: 10.3389/fimmu.2019.01813.
[20] 陈中, 张嘉玲, 杨歆萍, 等. 抑癌基因TP53及新家族成员TP63和TP73的研究新进展[J]. 内蒙古医科大学学报, 2013, 35(1): 57-62. doi:10.16343/j.cnki.issn.2095-512x.2013.01.014. CHEN Zhong, ZHANG Jialing, YANG Xinping, et al. The research progression of tumor suppressor tp53 and the new family members tp63 and tp73[J]. Acta Academiae Medicinae Neimongol, 2013, 35(1): 57-62. doi:10.16343/j.cnki.issn.2095-512x.2013.01.014.
[21] 何萌萌, 孙伟, 陈静, 等.细胞角蛋白5/6、P63蛋白、甲状腺转录因子-1、细胞角蛋白7在肺癌组织中的表达及意义[J]. 安徽医药, 2019, 23(5): 903-906,1063. doi:0.3969/j.issn.1009-6469.2019.05.016. HE Mengmeng, SUN Wei, CHEN Jing, et al. Expression and significance of CK5/6,P63,TTF-1 and CK7 in lung cancer[J]. Anhui Medical and Pharmaceutical Journal, 2019, 23(5): 903-906,1063. doi:0.3969/j.issn.1009-6469.2019.05.016.
[22] Lakshmanachetty S, Balaiya V, High WA, et al. Loss of TP63 promotes the metastasis of head and neck squamous cell carcinoma by activating MAPK and STAT3 signaling[J]. Mol Cancer Res, 2019, 17(6): 1279-1293. doi: 10.1158/1541-7786.MCR-18-1355.
[23] Lakshmanachetty S, Balaiya V, Johnson LK, et al. TRP63/TP63 loss accelerates skin tumorigenesis through activation of Wnt/β-catenin signaling[J]. J Dermatol Sci, 2018, 91(3): 325-328. doi:10.1016/j.jdermsci.2018.05.011.
[24] 梁羽, 谢建平, 温琥玲, 等, ESR1基因单核苷酸多态性与甲状腺乳头状癌临床易感的相关性研究[J]. 四川医学, 2017, 38(8): 899-902. doi: 10.16252/j.cnki.issn.1004-0501-2017.08.012. LIANG Yu, XIE Jianping, WEN Huling, et al. Association between single nucleotide polymorphism of ESR1 gene and clinical susceptibility of papillary thyroid carcinoma[J]. Sichuan Medical Journal, 2017, 38(8): 899-902. doi: 10.16252/j.cnki.issn.1004-0501-2017.08.012.
[1] WU Jing, LIU Yehai. Targeted therapy for head and neck squamous cell carcinoma [J]. J Otolaryngol Ophthalmol Shandong Univ, 2018, 32(5): 97-102.
[2] ZHAO Jincheng, SHI Ying, ZHANG Ying, JIA Zhanhong, MA Xin, ZHANG Jingqiu, WU Zaijun, WANG Yu. Expression and methylation patterns of CDH13 in human head and neck squamous carcinoma cells. [J]. JOURNAL OF SHANDONG UNIVERSITY (OTOLARYNGOLOGY AND OPHTHALMOLOGY), 2017, 31(4): 60-63.
[3] YU Zi-wei, DONG Pin, PANG Zheng. Clinical study of cetuximab combined with post-operative concurrent  chemo-radiotherapy on recurrent advanced squamous cell-carcinoma of the head and neck [J]. JOURNAL OF SHANDONG UNIVERSITY (OTOLARYNGOLOGY AND OPHTHALMOLOGY), 2010, 24(6): 44-46.
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