AUTHOR=Zhang Kehui , Wang Jian , Zhu YingYing , Liu Xiaolin , Li Jiacheng , Shi Zhe , Cao Mengxing , Li Yong 

TITLE=Identification of Hub Genes Associated With the Development of Stomach Adenocarcinoma by Integrated Bioinformatics Analysis

JOURNAL=Frontiers in Oncology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.844990

DOI=10.3389/fonc.2022.844990

ISSN=2234-943X

ABSTRACT=<sec><title>Objective</title><p>This study was conducted in order to gain a better understanding of the molecular mechanisms of stomach adenocarcinoma (STAD), which is necessary to predict the prognosis of STAD and develop novel gene therapy strategies.</p></sec><sec><title>Methods</title><p>In this study, the gene expression profile of GSE118916 in the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas Program (TCGA) was used to explore the differential co-expression genes of STAD and normal tissues.</p></sec><sec><title>Results</title><p>A total of 407 STAD samples were collected, consisting of 375 from stomach adenocarcinoma tissues and 32 from normal tissues, as well as RNA-seq count data for 19,600 genes. Forty-two differentially expressed genes were screened by weighted gene co-expression network analysis (WGCNA) and differentially expressed gene analysis. According to the functional annotation analysis of the clusterProfiler R package, these genes were analyzed for GO function enrichment, digestion (biological process), tube bottom material membrane (cell component), and oxidoreductase activity (molecular function). The KEGG pathway was enriched in gastric acid secretion and chemical carcinogenesis. In addition, Cytoscape’s cytoHubba plug-in was used to identify seven hub genes (<italic>EWSR1</italic>, <italic>ESR1</italic>, <italic>CLTC</italic>, <italic>PCMT1</italic>, <italic>TP53</italic>, <italic>HUWE1</italic>, and <italic>HDAC1</italic>) in a protein–protein interaction (PPI) network consisting of 7 nodes and 11 edges. Compared with normal tissues, <italic>CLTC</italic> and <italic>TP53</italic> genes were upregulated in stomach adenocarcinoma (<italic>P</italic> &lt; 0.05). <italic>TP53</italic> was expressed differently in stages II and IV, <italic>EWSR1</italic> was expressed differently in stages II and III, and <italic>ESR1</italic> was expressed differently in stages I–III. Among the seven hub genes, Kaplan–Meier analysis and TCGG showed that the expression levels of <italic>HDAC1</italic> and <italic>CLTC</italic> were significantly correlated with OS in patients with stomach adenocarcinoma (<italic>P</italic> &lt; 0.05). GEPIA2 analysis showed that <italic>ESR1</italic> expression was closely correlated with OS and DFS in gastric adenocarcinoma (<italic>P</italic> &lt; 0.05). Then, the expression of the genes and their correlations were revealed by the R2 Platform (<uri xlink:href="http://r2.amc.nl" xmlns:xlink="http://www.w3.org/1999/xlink">http://r2.amc.nl</uri>). Finally, we collected 18 pairs of gastric mucosal tissues from normal people and cancer tissues from patients with stomach adenocarcinoma. The expression levels of the above seven hub genes and their relative protein expression were detected by RT-PCR and immunohistochemistry (IHC). The results showed that the gene and protein expression levels in stomach adenocarcinoma tissues were increased than those in the normal group.</p></sec><sec><title>Conclusion</title><p>In summary, we believe that the identified hub genes were related to the occurrence of stomach adenocarcinoma, especially the expression of <italic>ESR1</italic>, <italic>HDAC1</italic>, and <italic>CLTC</italic> genes, which are related to the prognosis and overall survival of patients and may become the potential for the future diagnosis and treatment of STAD.</p></sec>