Abstract
Background/Objectives: Homeobox (HOX) genes encode conserved transcription factors essential for tissue and organ development and cellular differentiation. In humans, these genes are organized into four clusters: HOXA, HOXB, HOXC, and HOXD. While HOX genes have been extensively studied in cancer biology, their roles in esophageal squamous cell carcinoma (ESCC) remain poorly understood. Given the increasing incidence and high mortality rate of ESCC, exploring the molecular drivers of this tumor is urgent. Methods: Therefore, this study investigated the mutational landscape and expression profiles of HOX genes in ESCC and their differentially expressed targets using ESCC data from The Cancer Genome Atlas (TCGA) and two independent transcriptome datasets. Results: We found that copy number alterations and single nucleotide variations were rare, while seven HOX genes (HOXA2, HOXA7, HOXB13, HOXC9, HOXC10, HOXC13, and HOXD10) were significantly differentially expressed in ESCC compared to paired non-malignant mucosa. Further analysis identified 776 potential HOX target genes differentially expressed in ESCC, many of which are involved in critical cancer pathways such as PI3K-AKT, cell cycle regulation, and epithelial-mesenchymal transition (EMT). The HOXA7 overexpression was associated with poor overall survival rates in ESCC. This finding opens new possibilities for targeted therapies, offering hope for improved patient outcomes. Conclusions: Thus, this study underscored the pivotal role of HOX gene dysregulation in ESCC and classified HOXA7 as a potential prognostic biomarker in this tumor.