Poor Prognosis of Oral Squamous Cell Carcinoma Correlates With ITGA6

Abstract

Objectives: Oral cancer is the ninth most common cancer worldwide and a leading cause of cancer-related death. Oral squamous cell carcinoma (OSCC) accounts for 90% of all oral cancers. Autophagy is a conserved essential catabolic process related to OSCC. The aim of this study was to elucidate diagnostic and prognostic autophagy-related biomarkers in OSCC.

Methods: The OSCC gene expression data set was obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between the OSCC samples and adjacent healthy tissues were identified by R software. The Human Autophagy Database was screened, which revealed 222 autophagy-related genes. The autophagy-related DEGs were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were applied. Protein-protein interaction network analysis was performed in the STRING database. cytoHubba in the Cytoscape software was applied to determine the top 10 hub genes. The data set of patients with OSCC from The Cancer Genome Atlas (TCGA) was used to evaluate the prognostic value of the 10 hub genes. The association between prognosis-related hub genes and immune infiltrates was explored.

Results: Twenty-seven autophagy-related DEGs were identified. The top 10 hub genes were CCL2, CDKN2A, CTSB, CTSD, CXCR4, ITGA6, MAP1LC3A, MAPK3, PARP1, and RAB11A. ITGA6 was identified as the most efficient biomarker. Receiver operating characteristic curve analysis indicated that ITGA6 had the highest diagnostic accuracy for OSCC (area under the curve = 0.925). ITGA6 expression was significantly related to immune infiltrates.

Conclusions: The autophagy-related gene ITGA6 might be an efficient diagnostic and prognostic biomarker in OSCC.

Keywords: Autophagy; ITGA6; Oral squamous cell carcinoma.

Fig. 1

Identification of autophagy-related differentially expressed genes (DEGs) in oral squamous cell carcinoma (OSCC). A, mRNA expression level of each sample in the GSE74530. The degree of normalisation between samples was satisfactory. B, Principal component analysis plot indicates that there were significant differences between the groups. C, Volcano plot shows the DEG expression between OSCC and adjacent healthy tissues. Red points represent the up-regulated genes; blue points represent the down-regulated genes. A total of 1573 up-regulated genes and 613 down-regulated genes were identified. D, The heatmap shows the expression of the top 20 up-regulated genes and down-regulated genes. E, The Venn diagram shows the intersection of the DEGs and autophagy-related genes, including 27 genes, which are the autophagy-related DEGs. F, Spearman correlation analysis of the 27 autophagy-related DEGs.

Fig. 2

Functional enrichment analysis of autophagy-related differentially expressed genes (DEGs). A, Gene Ontology enrichment analysis of the 27 autophagy-related DEGs, including biological process, molecular function, and cellular component. B, The enriched Kyoto Encyclopedia of Genes and Genomes pathways of the 27 autophagy-related DEGs.

Fig. 3

Protein–protein interaction (PPI) network construction and identification of hub genes. A, STRING database was used for PPI analysis to identify the interaction between the autophagy-related differentially expressed genes (DEGs). B, The number of interactions of each gene with other genes is shown. C, The top 10 hub genes were identified through cytoHubba; they are CCL2, CDKN2A, CTSB, CTSD, CXCR4, ITGA6, MAP1LC3A, MAPK3, PARP1, and RAB11A. D, The expression level of the 10 hub genes in oral squamous cell carcinoma (OSCC) samples and healthy tissues, according to the data from The Cancer Genome Atlas–OSCC.

Fig. 4

Kaplan–Meier curves of overall survival of patients with oral squamous cell carcinoma (OSCC); patients were divided into a high-expression group and a low-expression group by the median of the expression data of the 10 hub genes from The Cancer Genome Atlas–OSCC. A, High expression of ITGA6 was related to lower overall survival of patients with OSCC, P = .043. B–J, The expression of CCL2 (P = .832), CDKN2A (P = .105), CTSB (P = .983), CTSD (P = .258), CXCR4 (P = .881), MAP1LC3A (P = .367), MAPK3 (P = .158), PARP1 (P = .254), and RAB11A (P = .067) did not significantly influence the overall survival of patients with OSCC.

Fig. 5

Receiver operating characteristic analysis indicated the diagnostic accuracy value of the 10 hub genes. A, The diagnostic accuracy value of ITGA6 was highest, with area under the curve (AUC) = 0.925. B–J, The diagnostic accuracy values of the other 9 hub genes were as follows: CCL2 (AUC = 0.786), CDKN2A (AUC = 0.693), CTSB (AUC = 0.768), CTSD (AUC = 0.657), CXCR4 (AUC = 0.579), MAP1LC3A (AUC = 0.711), MAPK3 (AUC = 0.744), PARP1 (AUC = 0.813), and RAB11A (AUC = 0.707).