LAUSR

Simple Summary Keratins are the intermediate filament-forming proteins of epithelial cells that support cell structure and tissue homeostasis. In lung squamous cell cancer, keratins are frequently used as diagnostic tumor markers. However, several studies have shown evidence of keratin’s roles in cancer invasion, metastasis, and therapy resistance. In this study, we aimed to identify key regulators of the cancer-related keratinization process in LUSC. Our findings may help others to gain insight into the cancer-related keratinization process and to find potential targets for diagnostics and therapy for LUSC. Abstract Keratinization is one of lung squamous cell cancer’s (LUSC) hallmark histopathology features. Epithelial cells produce keratin to protect their integrity from external harmful substances. In addition to their roles as cell protectors, recent studies have shown that keratins have important roles in regulating either normal cell or tumor cell functions. The objective of this study is to identify the genes and microRNAs (miRNAs) that act as key regulators of the keratinization process in LUSC. To address this goal, we classified LUSC samples from GDC-TCGA databases based on their keratinization molecular signatures. Then, we performed differential analyses of genes, methylation, and miRNA expression between high keratinization and low keratinization samples. By reconstruction and analysis of the differentially expressed genes (DEGs) network, we found that TP63 and SOX2 were the hub genes that were highly connected to other genes and displayed significant correlations with several keratin genes. Methylation analysis showed that the P63, P73, and P53 DNA-binding motif sites were significantly enriched for differentially methylated probes. We identified SNAI2, GRHL3, TP63, ZNF750, and FOXE1 as the top transcription factors associated with these binding sites. Finally, we identified 12 miRNAs that influence the keratinization process by using miRNA–mRNA correlation analysis.