Identifying Key Regulators of Keratinization in Lung Squamous Cell Cancer Using Integrated TCGA Analysis

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.

Transcriptomic Profiling for Prognostic Biomarkers in Early-Stage Squamous Cell Lung Cancer (SqCLC)

“…It is known that keratin filaments play a role in forming the protein structural framework within the epithelial cells and protecting them from different types of stressors [33]. Keratins are also a characteristic feature of early-stage SqCLC, while reduced in lung adenocarcinoma [34], and are extensively used as specific diagnostic markers for different tumor types, including squamous cell carcinomas, which are characterized by keratinocyte hyperproliferation [35]. Another interesting finding is FOXM1 overexpression, a transcription factor that plays a critical role in normal lung development, affecting the differentiation and function of lung epithelial cells.…”