Low FOXA2 Expression Is Associated With ECM Remodeling, FAK--YAP-Related Transcriptional Features, and a Macrophage-Enriched Immune-Stromal Microenvironment in Hepatocellular Carcinoma

Abstract

Tumor-associated macrophages and extracellular matrix remodeling are important components shaping the microenvironment of hepatocellular carcinoma (HCC). This study examined whether forkhead box A2 (FOXA2) expression is associated with extracellular matrix (ECM)/stromal remodeling, focal adhesion kinase (FAK)--Yes-associated protein (YAP)-related transcriptional features, and immune-stromal characteristics in HCC. Using The Cancer Genome Atlas liver hepatocellular carcinoma (TCGA-LIHC) cohort for discovery and the ICGC-LIRI-JP and GSE14520 datasets for expression validation, we performed differential expression, enrichment analysis, single-sample gene set scoring, ESTIMATE-based microenvironment assessment, and Cox regression, with FOXA2-high and FOXA2-low groups defined by the cohort-specific median. FOXA2 expression was consistently reduced in HCC tissues and associated with unfavorable overall survival (log-rank $P = 0.006$). FOXA2-low tumors showed higher ECM/stromal remodeling and FAK--YAP-related scores, enrichment of fibroblast, M2 macrophage, regulatory T-cell, endothelial, and immune checkpoint-related signatures, and decreased CD8-positive T-cell and M1 macrophage signatures; exploratory enrichment also indicated altered lipid metabolism-related programs. These co-occurring bulk features do not establish a causal FOXA2--ECM--FAK--YAP--immune pathway. Low FOXA2 expression therefore marks an HCC transcriptional state characterized by stromal remodeling, mechanotransduction-related features, and immunosuppressive signatures. Single-cell, spatial, protein-level, and functional validation is required to determine the underlying cellular origin and mechanism.