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Prognostic Role of DFNA5 in Head and Neck Squamous Cell Carcinoma

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Prognostic Role of DFNA5 in Head and Neck Squamous Cell Carcinoma Liu et al. BMC Cancer (2021) 21:951 https://doi.org/10.1186/s12885-021-08692-w RESEARCH Open Access Prognostic role of DFNA5 in head and neck squamous cell carcinoma revealed by systematic expression analysis Zhiguo Liu1,2†, Hongyan Liu2,3†, Qian Dong1,2, Hongyu Li1,2, Bin Zhang1,2, Yufeng Liu4, Limei Zhong5* and Haikuo Tang1,2* Abstract Background: The gasdermin E gene (GSDME, also known as DFNA5) is mutated in familial aging-related hearing loss. Recent studies have also revealed that the expression of DFNA5 is suppressed in many cancer types; however, little is known about the function of DFNA5 in head and neck squamous cell carcinoma (HNSCC). Accordingly, the aim of the present study was to evaluate the expression of DFNA5 and explore its prognostic value in HNSCC. Result: We used a set of bioinformatics tools, including Oncomine, TIMER, TISIDB, cBioPortal, and GEPIA, to analyze the expression of DFNA5 in patients with HNSCC from public databases. Kaplan-Meier plotter was used to evaluate the potential prognostic significance of DFNA5. DFNA5 mRNA levels were significantly higher in HNSCC tissues than in normal tissues, and high DFNA5 expression was correlated with worse survival. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that DFNA5 expression has a strong positive correlation with cell adhesion and the integrin signaling pathway, whereas its expression was negatively correlated with the levels of infiltrating B cells (cor = − 0.223, P = 8.57e-07) and CD8 T cells (cor = − 0.223, P = 2.99e-07). Conclusion: This study demonstrates that DFNA5 expression has prognostic value for HNSCC patients. Moreover, these results suggest that regulation of lymphocyte infiltration is the mechanism underlying the function of DFNA5 in HNSCC. Keywords: DFNA5, Head and neck cancer, Survival prognosis, Lymphocyte infiltration Introduction and larynx [1, 2]. Approximately 600,000 new cases of Head and neck cancers include a wide variety of cancers HNSCC are diagnosed each year worldwide, often at an varying in location and histological types. One of the advanced stage. Moreover, epidemiological data indicate subcategories is head and neck squamous cell carcin- that the incidence of oral cancer is increasing year after omas (HNSCCs), which include tumors of the nasal cav- year [3]. Although the use of combination therapy (i.e., ity, nasopharynx, oral cavity, oropharynx, hypopharynx, surgical techniques, chemotherapy, and radiation ther- apy) has significantly improved local control and the overall quality of life of HNSCC patients, their survival * Correspondence: [email protected]; [email protected] † rate has only increased slightly in the past 20 years [4]. Zhiguo Liu and Hongyan Liu contributed equally to this work. 5Department of Laboratory Medicine, Guangdong Second Provincial General Therefore, it is imperative to understand the potential Hospital, No. 466 Xingang Middle Road, Haizhu District, Guangzhou 510317, molecular carcinogenic pathways of HNSCC, which is China expected to identify markers that can help to improve 1Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Sun Yat-sen University, 56 Lingyuanxi Road, Guangzhou 510055, China the diagnosis, treatment, and prevention of the disease. Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Liu et al. BMC Cancer (2021) 21:951 Page 2 of 12 Gasdermin E (GSDME), also known as deafness auto- users can cross check the gene of interest through know- somal dominant 5 (DFNA5), was identified as a gene in- ledge from different platforms and obtain high quality volved in an autosomal dominant form of inherited visualization results for their publications (http://cis.hku. hearing impairment in 1998 [5]. Interestingly, subse- hk/TISIDB/)[12]. In present study, we use TISIDB to quent reports showed that DFNA5 also plays a role in predict the prognosis evaluation. tumor biology. Specifically, DFNA5 has been suggested to act as a tumor suppressor, since it was shown to in- cBioPortal hibit the colony formation and cell proliferation of gas- cBioPortal includes tools for the visualization, analysis, tric cancer, melanoma, and colorectal cancer cells, and and downloading of large-scale cancer genomics data- could also suppress the aggressive behavior of breast sets. In order to regulatory network of DFNA5, we used cancer [6]. Recently, some chemotherapeutic agents such cBioPortal to identify genes positively related to DFNA5 as cisplatin [7], L61H10 [8], and lobaplatin [9] were expression in HNSCC [13]. shown to be effective against esophageal cancer, lung cancer, and colon cancer, respectively, by inducing a DFNA5-dependent pyroptosis effect. These results have GEPIA led to a new understanding of cancer chemotherapy, GEPIA (http://gepia.pku.cn/) is a newly developed inter- while indicating that DFNA5 is a potential target for active web server for analyzing the RNA sequencing ex- cancer treatment. However, the role of DFNA5 in HNSC pression data of 9736 tumors and 8587 normal samples C development and progression remains unknown. from the TCGA and the GTEx projects, using a standard In this work, we applied a wide range of comprehen- processing pipeline. GEPIA provides customizable func- sive bioinformatics tools to assess the expression levels tions such as tumor/normal differential expression ana- and potential function of DFNA5, as well as determine lysis, profiling according to cancer types or pathological its prognostic value in human HNSCC. stages, patient survival analysis, similar gene detection, correlation analysis and dimensionality reduction ana- Materials and methods lysis. In present study, GEPIA was used to analysis dif- Oncomine ferential expression and survival analyses [14]. In order to evaluate the expression of DFNA5 in differ- ent tumors, Oncomine (https://www.oncomine.org/ Kaplan-Meier plotter resource/login.html) is a publicly accessible online can- The Kaplan Meier plotter is capable to assess the effect cer microarray database that can be used for research re- of 54 k genes (mRNA, miRNA, protein) on survival in 21 lated to genome-wide expression analysis. We used this cancer types. Sources for the databases include GEO, database to extract data on the DFNA5 mRNA levels EGA, and TCGA. Primary purpose of the tool is a meta- (log2-transformed) in HNSCC and neighboring normal analysis based discovery and validation of survival bio- tissues. The criteria for identifying a significant differ- markers. Kaplan-Meier plotter (http://kmplot.com/ ence were a P-value <1E-4, fold change > 2, and the gene analysis/) was used to evaluate the potential prognostic ranks in the top 10% [10]. significance of DFNA5 [15]. The hazard ratio (HR) with a 95% confidence interval and the P-value (log-rank) Timer were calculated. To research the relationship between TIMER is a web server for the comprehensive analysis of the DFNA5 expression level and specific clinical charac- expression pattern and tumor-infiltrating immune cells. teristics of HNSCC patients. Enter DFNA5 in the web- It offers six tumor-infiltrating immune subsets precalcu- site of Kaplan-Meier plotter, select HNSCC in Pan- lated for 10,897 tumors from 32 cancer types (https:// cancer RNA-seq database, and then select the corre- cistrome.shinyapps.io/timer/)[11]. TIMER web server sponding index (as shown in Table 2) in the right-hand allows users to input function-specific parameters, with border, click draw Kaplan-Meier plot to record the cor- resulting figures dynamically displayed to conveniently responding results. access the tumor immunological, clinical, and genomic features. Cytoscape TISIDB Cytoscape (version 3.4.0) is an open-source bioinformat- TISIDB is an integrated repository portal for tumor- ics software tool for visualizing molecular interaction immune system interactions, which can also be used for networks. Its plug-in, MCODE, is used for ranking the systematic testing of molecular features of such in- nodes in a network according to their network features teractions TISIDB is the most comprehensive database [16]. Presently, we use Cytoscape to study the regulatory for tumor and immune system interactions. In TISIDB, network of DFNA5 in HNSCC. Liu et al. BMC Cancer (2021) 21:951 Page 3 of 12 David correlation of gene expression in TIMER, LinkedOmics DAVID (http://david.abcc.ncifcrf.gov/) is a tool that is and UALCAN databases. *P < 0.05, **P < 0.01, ***P < widely used to reveal the biological significance of gene 0.001 was considered statistically significant. groups. After selecting co-expressed genes, Gene Ontol- The list of experiments were listed in Table 1. ogy (GO) analysis was performed to assess their associ- ated biological processes (BP), cellular components Results (CC), and molecular functions (MF) [17]. The Kyoto DFNA5 expression is upregulated in human HNSCC Encyclopedia of Genes and Genomes (KEGG) pathway The analysis of microarray data from HNSCC and adja- database was used to identify biological pathways cent normal tissues in the Oncomine database showed enriched with the co-expressed genes [18].
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