Identification of Biomarkers Associated with Cancerous Change in Oral Leukoplakia Based on Integrated Transcriptome Analysis

Abstract

Objective. Oral leukoplakia (OLK) is the most common precancerous lesion in the oral cavity. This study aimed to explore key biomarkers for monitoring OLK for early diagnosis of oral squamous cell carcinoma (OSCC) and screen small-molecule drugs for the prevention of OSCC. Method. The Gene Expression Omnibus (GEO) database was explored to extract two microarray datasets, namely, GSE85195 and GSE25099. The data of the normal group, OLK group, and OSCC group were analyzed by weighted gene coexpression network analysis (WGCNA) to identify the most significant gene module and differentially expressed genes (DEGs). The intersection genes were extracted as the key genes of OLK carcinogenesis. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were analyzed in the module. Connectivity Map and molecular docking were used to screen small-molecule drugs. The diagnostic values of four key genes were identified and verified in the GSE26549 dataset. Results. WGCNA obtained the red module (r = -0.91, p<0.05) with the strongest correlation with cancerous phenotype. GO enrichment analysis showed 60 pathways, including 28 biological processes, 11 cell components, and 21 molecular functions, and KEGG enrichment analysis showed 4 pathways (p<0.05). In the differential expression analysis, there was no intersection between the upregulated genes and the red module genes. However, the intersection of the downregulated genes and the red module genes yielded 4 key genes: dopachrome tautomerase (DCT), keratin 3 (KRT3), keratin 76 (KRT76), and FAM3 metabolic regulation signal molecule B (FAM3B). The area under the curve of the diagnostic model constructed by these four genes was 0.963 (CI = 0.913-1.000). The sensitivity was 0.933, and the specificity was 0.923. The diagnostic model was successfully verified in GSE26549 (AUC = 0.745, CI = 0.638-0.851). Compared with the diagnostic models of the previous studies, the diagnostic efficiency of this model was the highest. The small-molecule drugs, selumetinib and benidipine, were selected according to the gene expression profile and showed binding activity when docking with the above molecules. Conclusions. This study provides new targets and drugs for OLK. These targets could be used as the key diagnostic molecules for long-term follow-up of OLK. The small-molecule drugs selumetinib and benidipine could be used for the prevention and treatment of OSCC.