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Published in: Cancer Cell International 1/2021

01-12-2021 | Hypopharyngeal Cancer | Primary research

Identification of key genes for HNSCC from public databases using bioinformatics analysis

Authors: Yuchu Ye, Jingyi Wang, Faya Liang, Pan Song, Xiaoqing Yan, Sangqing Wu, Xiaoming Huang, Ping Han

Published in: Cancer Cell International | Issue 1/2021

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Abstract

Background

The cause and underlying molecular mechanisms of head and neck squamous cell carcinoma (HNSCC) are unclear. Our study aims to identify the key genes associated with HNSCC and reveal potential biomarkers.

Methods

In this study, the expression profile dataset GSE83519 of the Gene Expression Omnibus database and the RNA sequencing dataset of HNSCC of The Cancer Genome Atlas were included for analysis. Sixteen differentially expressed genes were screened from these two datasets using R software. Gene Expression Profiling Interactive Analysis 2 (GEPIA2) was then adopted for survival analysis, and finally, three key genes related to the overall survival of HNSCC patients were identified. Furthermore, we verified these three genes using the Oncomine database and from real-time PCR and immunohistochemistry results from HNSCC tissues.

Results

The expression data of 44 samples from GSE83519 and 545 samples from TCGA-HNSC were collected. Using bioinformatics, the two databases were integrated, and 16 DEGs were screened out. Gene Ontology (GO) enrichment analysis showed that the biological functions of DEGs focused primarily on the apical plasma membrane and regulation of anoikis. Kyoto Encyclopedia of Genes and Genomes (KEGG) signalling pathway analysis showed that these DEGs were mainly involved in drug metabolism-cytochrome P450 and serotonergic synapses. Survival analysis identified three key genes, CEACAM5, CEACAM6 and CLCA4, that were closely related to HNSCC prognosis. The Oncomine database, qRT–PCR and IHC verified that all 3 key genes were downregulated in most HNSCC tissues compared to adjacent normal tissues.

Conclusions

This study indicates that integrated bioinformatics analyses play an important role in screening for differentially expressed genes and pathways in HNSCC, helping us better understand the biomarkers and molecular mechanism of HNSCC.
Literature
1.
go back to reference Gupta B, Johnson NW, Kumar N. Global epidemiology of head and neck cancers: a continuing challenge. Oncology. 2016;91(1):13–23.PubMedCrossRef Gupta B, Johnson NW, Kumar N. Global epidemiology of head and neck cancers: a continuing challenge. Oncology. 2016;91(1):13–23.PubMedCrossRef
2.
go back to reference Colevas AD, Yom SS, Pfister DG, Spencer S, Adelstein D, Adkins D, et al. NCCN guidelines insights: head and neck cancers, version 1.2018. J Natl Compr Canc Netw. 2018;16(5):479–90.PubMedCrossRef Colevas AD, Yom SS, Pfister DG, Spencer S, Adelstein D, Adkins D, et al. NCCN guidelines insights: head and neck cancers, version 1.2018. J Natl Compr Canc Netw. 2018;16(5):479–90.PubMedCrossRef
3.
go back to reference Duprez F, Berwouts D, De Neve W, Bonte K, Boterberg T, Deron P, et al. Distant metastases in head and neck cancer. Head Neck. 2017;39(9):1733–43.PubMedCrossRef Duprez F, Berwouts D, De Neve W, Bonte K, Boterberg T, Deron P, et al. Distant metastases in head and neck cancer. Head Neck. 2017;39(9):1733–43.PubMedCrossRef
4.
go back to reference Leeman JE, Li JG, Pei X, Venigalla P, Zumsteg ZS, Katsoulakis E, et al. Patterns of treatment failure and postrecurrence outcomes among patients with locally advanced head and neck squamous cell carcinoma after chemoradiotherapy using modern radiation techniques. JAMA Oncol. 2017;3(11):1487–94.PubMedPubMedCentralCrossRef Leeman JE, Li JG, Pei X, Venigalla P, Zumsteg ZS, Katsoulakis E, et al. Patterns of treatment failure and postrecurrence outcomes among patients with locally advanced head and neck squamous cell carcinoma after chemoradiotherapy using modern radiation techniques. JAMA Oncol. 2017;3(11):1487–94.PubMedPubMedCentralCrossRef
5.
go back to reference Vokes EE, Agrawal N, Seiwert TY. HPV-associated head and neck cancer. J Natl Cancer Inst. 2015;107(12):djv344.PubMedCrossRef Vokes EE, Agrawal N, Seiwert TY. HPV-associated head and neck cancer. J Natl Cancer Inst. 2015;107(12):djv344.PubMedCrossRef
6.
go back to reference Leemans CR, Snijders PJF, Brakenhoff RH. The molecular landscape of head and neck cancer. Nat Rev Cancer. 2018;18(5):269–82.PubMedCrossRef Leemans CR, Snijders PJF, Brakenhoff RH. The molecular landscape of head and neck cancer. Nat Rev Cancer. 2018;18(5):269–82.PubMedCrossRef
9.
10.
go back to reference Zhang L, Li B, Peng Y, Wu F, Li Q, Lin Z, et al. The prognostic value of TMB and the relationship between TMB and immune infiltration in head and neck squamous cell carcinoma: a gene expression-based study. Oral Oncol. 2020;110:104943.PubMedCrossRef Zhang L, Li B, Peng Y, Wu F, Li Q, Lin Z, et al. The prognostic value of TMB and the relationship between TMB and immune infiltration in head and neck squamous cell carcinoma: a gene expression-based study. Oral Oncol. 2020;110:104943.PubMedCrossRef
11.
go back to reference Wang J, Chen X, Tian Y, Zhu G, Qin Y, Chen X, et al. Six-gene signature for predicting survival in patients with head and neck squamous cell carcinoma. Aging. 2020;12(1):767–83.PubMedPubMedCentralCrossRef Wang J, Chen X, Tian Y, Zhu G, Qin Y, Chen X, et al. Six-gene signature for predicting survival in patients with head and neck squamous cell carcinoma. Aging. 2020;12(1):767–83.PubMedPubMedCentralCrossRef
12.
go back to reference Mantione KJ, Kream RM, Kuzelova H, Ptacek R, Raboch J, Samuel JM, et al. Comparing bioinformatic gene expression profiling methods: microarray and RNA-Seq. Med Sci Monit Basic Res. 2014;20:138–42.PubMedPubMedCentralCrossRef Mantione KJ, Kream RM, Kuzelova H, Ptacek R, Raboch J, Samuel JM, et al. Comparing bioinformatic gene expression profiling methods: microarray and RNA-Seq. Med Sci Monit Basic Res. 2014;20:138–42.PubMedPubMedCentralCrossRef
14.
go back to reference Segundo-Val IS, Sanz-Lozano CS. Introduction to the gene expression analysis. Methods Mol Biol. 2016;1434:29–43.PubMedCrossRef Segundo-Val IS, Sanz-Lozano CS. Introduction to the gene expression analysis. Methods Mol Biol. 2016;1434:29–43.PubMedCrossRef
15.
go back to reference Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, et al. NCBI GEO: archive for functional genomics data sets–update. Nucleic Acids Res. 2013;41(D1):D991-5.PubMedCrossRef Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, et al. NCBI GEO: archive for functional genomics data sets–update. Nucleic Acids Res. 2013;41(D1):D991-5.PubMedCrossRef
16.
go back to reference Edgar R, Domrachev M, Lash AE. Gene expression omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2002;30(1):207–10.PubMedPubMedCentralCrossRef Edgar R, Domrachev M, Lash AE. Gene expression omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2002;30(1):207–10.PubMedPubMedCentralCrossRef
17.
go back to reference Cancer Genome Atlas N. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517(7536):576–82.CrossRef Cancer Genome Atlas N. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517(7536):576–82.CrossRef
19.
go back to reference Kanehisa M, Furumichi M, Tanabe M, Sato Y, Morishima K. KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 2017;45(D1):D353–61.PubMedCrossRef Kanehisa M, Furumichi M, Tanabe M, Sato Y, Morishima K. KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 2017;45(D1):D353–61.PubMedCrossRef
20.
go back to reference Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47(D1):D607–13.PubMedCrossRef Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47(D1):D607–13.PubMedCrossRef
21.
go back to reference Tang Z, Kang B, Li C, Chen T, Zhang Z. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 2019;47(W1):W556–60.PubMedPubMedCentralCrossRef Tang Z, Kang B, Li C, Chen T, Zhang Z. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 2019;47(W1):W556–60.PubMedPubMedCentralCrossRef
22.
go back to reference Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, et al. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia. 2004;6(1):1–6.PubMedPubMedCentralCrossRef Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, et al. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia. 2004;6(1):1–6.PubMedPubMedCentralCrossRef
23.
go back to reference World Medical A. World medical association declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191–4.CrossRef World Medical A. World medical association declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191–4.CrossRef
24.
go back to reference Yu ST, Zhong Q, Chen RH, Han P, Li SB, Zhang H, et al. CRLF1 promotes malignant phenotypes of papillary thyroid carcinoma by activating the MAPK/ERK and PI3K/AKT pathways. Cell Death Dis. 2018;9(3):371.PubMedPubMedCentralCrossRef Yu ST, Zhong Q, Chen RH, Han P, Li SB, Zhang H, et al. CRLF1 promotes malignant phenotypes of papillary thyroid carcinoma by activating the MAPK/ERK and PI3K/AKT pathways. Cell Death Dis. 2018;9(3):371.PubMedPubMedCentralCrossRef
25.
go back to reference Han P, Chen RH, Wang F, Zeng JY, Yu ST, Xu LH, et al. Novel chimeric transcript RRM2-c2orf48 promotes metastasis in nasopharyngeal carcinoma. Cell Death Dis. 2017;8(9): e3047.PubMedPubMedCentralCrossRef Han P, Chen RH, Wang F, Zeng JY, Yu ST, Xu LH, et al. Novel chimeric transcript RRM2-c2orf48 promotes metastasis in nasopharyngeal carcinoma. Cell Death Dis. 2017;8(9): e3047.PubMedPubMedCentralCrossRef
27.
go back to reference Tomczak K, Czerwińska P, Wiznerowicz M. The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge. Contemp Oncol. 2015;19(1a):A68-77. Tomczak K, Czerwińska P, Wiznerowicz M. The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge. Contemp Oncol. 2015;19(1a):A68-77.
28.
go back to reference Cohen EEW, Licitra LF, Burtness B, Fayette J, Gauler T, Clement PM, et al. Biomarkers predict enhanced clinical outcomes with afatinib versus methotrexate in patients with second-line recurrent and/or metastatic head and neck cancer. Ann Oncol. 2017;28(10):2526–32.PubMedPubMedCentralCrossRef Cohen EEW, Licitra LF, Burtness B, Fayette J, Gauler T, Clement PM, et al. Biomarkers predict enhanced clinical outcomes with afatinib versus methotrexate in patients with second-line recurrent and/or metastatic head and neck cancer. Ann Oncol. 2017;28(10):2526–32.PubMedPubMedCentralCrossRef
29.
go back to reference Morris LGT, Chandramohan R, West L, Zehir A, Chakravarty D, Pfister DG, et al. The Molecular landscape of recurrent and metastatic head and neck cancers insights from a precision oncology sequencing platform. JAMA Oncol. 2017;3(2):244–55.PubMedPubMedCentralCrossRef Morris LGT, Chandramohan R, West L, Zehir A, Chakravarty D, Pfister DG, et al. The Molecular landscape of recurrent and metastatic head and neck cancers insights from a precision oncology sequencing platform. JAMA Oncol. 2017;3(2):244–55.PubMedPubMedCentralCrossRef
30.
go back to reference Wong N, Khwaja SS, Baker CM, Gay HA, Thorstad WL, Daly MD, et al. Prognostic microRNA signatures derived from The Cancer Genome Atlas for head and neck squamous cell carcinomas. Cancer Med. 2016;5(7):1619–28.PubMedPubMedCentralCrossRef Wong N, Khwaja SS, Baker CM, Gay HA, Thorstad WL, Daly MD, et al. Prognostic microRNA signatures derived from The Cancer Genome Atlas for head and neck squamous cell carcinomas. Cancer Med. 2016;5(7):1619–28.PubMedPubMedCentralCrossRef
31.
go back to reference Concha-Benavente F, Srivastava RM, Trivedi S, Lei Y, Chandran U, Seethala RR, et al. Identification of the cell-intrinsic and -extrinsic pathways downstream of EGFR and IFN gamma that induce PD-L1 expression in head and neck cancer. Can Res. 2016;76(5):1031–43.CrossRef Concha-Benavente F, Srivastava RM, Trivedi S, Lei Y, Chandran U, Seethala RR, et al. Identification of the cell-intrinsic and -extrinsic pathways downstream of EGFR and IFN gamma that induce PD-L1 expression in head and neck cancer. Can Res. 2016;76(5):1031–43.CrossRef
32.
go back to reference Zhou J, Fan X, Chen N, Zhou F, Dong J, Nie Y, et al. Identification of CEACAM5 as a biomarker for prewarning and prognosis in gastric cancer. J Histochem Cytochem. 2015;63(12):922–30.PubMedPubMedCentralCrossRef Zhou J, Fan X, Chen N, Zhou F, Dong J, Nie Y, et al. Identification of CEACAM5 as a biomarker for prewarning and prognosis in gastric cancer. J Histochem Cytochem. 2015;63(12):922–30.PubMedPubMedCentralCrossRef
33.
go back to reference Wang XM, Zhang Z, Pan LH, Cao XC, Xiao C. KRT19 and CEACAM5 mRNA-marked circulated tumor cells indicate unfavorable prognosis of breast cancer patients. Breast Cancer Res Treat. 2019;174(2):375–85.PubMedCrossRef Wang XM, Zhang Z, Pan LH, Cao XC, Xiao C. KRT19 and CEACAM5 mRNA-marked circulated tumor cells indicate unfavorable prognosis of breast cancer patients. Breast Cancer Res Treat. 2019;174(2):375–85.PubMedCrossRef
34.
go back to reference Chen J, Li Q, An Y, Lv N, Xue X, Wei J, et al. CEACAM6 induces epithelial-mesenchymal transition and mediates invasion and metastasis in pancreatic cancer. Int J Oncol. 2013;43(3):877–85.PubMedCrossRef Chen J, Li Q, An Y, Lv N, Xue X, Wei J, et al. CEACAM6 induces epithelial-mesenchymal transition and mediates invasion and metastasis in pancreatic cancer. Int J Oncol. 2013;43(3):877–85.PubMedCrossRef
35.
go back to reference Cameron S, de Long LM, Hazar-Rethinam M, Topkas E, Endo-Munoz L, Cumming A, et al. Focal overexpression of CEACAM6 contributes to enhanced tumourigenesis in head and neck cancer via suppression of apoptosis. Mol Cancer. 2012;11:74.PubMedPubMedCentralCrossRef Cameron S, de Long LM, Hazar-Rethinam M, Topkas E, Endo-Munoz L, Cumming A, et al. Focal overexpression of CEACAM6 contributes to enhanced tumourigenesis in head and neck cancer via suppression of apoptosis. Mol Cancer. 2012;11:74.PubMedPubMedCentralCrossRef
36.
go back to reference Ginos MA, Page GP, Michalowicz BS, Patel KJ, Volker SE, Pambuccian SE, et al. Identification of a gene expression signature associated with recurrent disease in squamous cell carcinoma of the head and neck. Cancer Res. 2004;64(1):55–63.PubMedCrossRef Ginos MA, Page GP, Michalowicz BS, Patel KJ, Volker SE, Pambuccian SE, et al. Identification of a gene expression signature associated with recurrent disease in squamous cell carcinoma of the head and neck. Cancer Res. 2004;64(1):55–63.PubMedCrossRef
37.
go back to reference Cromer A, Carles A, Millon R, Ganguli G, Chalmel F, Lemaire F, et al. Identification of genes associated with tumorigenesis and metastatic potential of hypopharyngeal cancer by microarray analysis. Oncogene. 2004;23(14):2484–98.PubMedCrossRef Cromer A, Carles A, Millon R, Ganguli G, Chalmel F, Lemaire F, et al. Identification of genes associated with tumorigenesis and metastatic potential of hypopharyngeal cancer by microarray analysis. Oncogene. 2004;23(14):2484–98.PubMedCrossRef
38.
39.
go back to reference Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE. CEACAM6 gene silencing impairs anoikis resistance and in vivo metastatic ability of pancreatic adenocarcinoma cells. Oncogene. 2004;23(2):465–73.PubMedCrossRef Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE. CEACAM6 gene silencing impairs anoikis resistance and in vivo metastatic ability of pancreatic adenocarcinoma cells. Oncogene. 2004;23(2):465–73.PubMedCrossRef
40.
go back to reference Kim KS, Kim JT, Lee SJ, Kang MA, Choe IS, Kang YH, et al. Overexpression and clinical significance of carcinoembryonic antigen-related cell adhesion molecule 6 in colorectal cancer. Clin Chim Acta. 2013;415:12–9.PubMedCrossRef Kim KS, Kim JT, Lee SJ, Kang MA, Choe IS, Kang YH, et al. Overexpression and clinical significance of carcinoembryonic antigen-related cell adhesion molecule 6 in colorectal cancer. Clin Chim Acta. 2013;415:12–9.PubMedCrossRef
41.
go back to reference Bednarek K, Kostrzewska-Poczekaj M, Szaumkessel M, Kiwerska K, Paczkowska J, Byzia E, et al. Downregulation of CEACAM6 gene expression in laryngeal squamous cell carcinoma is an effect of DNA hypermethylation and correlates with disease progression. Am J Cancer Res. 2018;8(7):1249–61.PubMedPubMedCentral Bednarek K, Kostrzewska-Poczekaj M, Szaumkessel M, Kiwerska K, Paczkowska J, Byzia E, et al. Downregulation of CEACAM6 gene expression in laryngeal squamous cell carcinoma is an effect of DNA hypermethylation and correlates with disease progression. Am J Cancer Res. 2018;8(7):1249–61.PubMedPubMedCentral
42.
go back to reference Chen H, Liu Y, Jiang CJ, Chen YM, Li H, Liu QA. Calcium-activated chloride channel A4 (CLCA4) plays inhibitory roles in invasion and migration through suppressing epithelial–mesenchymal transition via PI3K/AKT signaling in colorectal cancer. Med Sci Monit. 2019;25:4176–85.PubMedPubMedCentralCrossRef Chen H, Liu Y, Jiang CJ, Chen YM, Li H, Liu QA. Calcium-activated chloride channel A4 (CLCA4) plays inhibitory roles in invasion and migration through suppressing epithelial–mesenchymal transition via PI3K/AKT signaling in colorectal cancer. Med Sci Monit. 2019;25:4176–85.PubMedPubMedCentralCrossRef
43.
go back to reference Chen YP, Chan ATC, Le QT, Blanchard P, Sun Y, Ma J. Nasopharyngeal carcinoma. Lancet. 2019;394(10192):64–80.PubMedCrossRef Chen YP, Chan ATC, Le QT, Blanchard P, Sun Y, Ma J. Nasopharyngeal carcinoma. Lancet. 2019;394(10192):64–80.PubMedCrossRef
Metadata
Title
Identification of key genes for HNSCC from public databases using bioinformatics analysis
Authors
Yuchu Ye
Jingyi Wang
Faya Liang
Pan Song
Xiaoqing Yan
Sangqing Wu
Xiaoming Huang
Ping Han
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2021
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-021-02254-7

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