Tumor Endothelial Cells-Associated Integrin Alpha-6 as a Promising Biomarker for Early Detection and Prognosis of Hepatocellular Carcinoma

SIMPLE SUMMARY: This study aims to validate the integrin alpha-6 (ITGA6) gene as a potential blood marker for early detection of hepatocellular carcinoma (HCC). Our methodological approach involved analyzing genomic datasets, leading to the identification of ITGA6 among differentially expressed genes in HCC. Further validation and analyses revealed consistent upregulation of ITGA6 in HCC, its predominant expression in tumor endothelial cells (TECs), and associations with pro-tumorigenic immune cells. This research highlights the potential of ITGA6 as an early HCC detection marker and its role in the tumor microenvironment, paving the way for new strategies in HCC management. ABSTRACT: HCC remains a lethal cancer type, with early detection being critical for improved patient outcomes. This study introduces a comprehensive methodological approach to identify the ITGA6 gene as a potential blood marker for early HCC (eHCC) detection. We initially analyzed the GSE114564 dataset encompassing various stages of liver disease, identifying 972 differentially expressed genes in HCC. A refined analysis yielded 59 genes specifically differentially expressed in early HCC, including ITGA6. Subsequent validation in multiple datasets confirmed the consistent upregulation of ITGA6 in HCC. In addition, when analyzing progression-free survival (PFS) within the entire patient cohort and overall survival (OS) specifically among patients classified as tumor grade G1, the group of patients characterized by high expression levels of ITGA6 displayed an elevated risk ratio in relation to prognosis. Further analyses demonstrated the predominant expression of ITGA6 in TECs and its enrichment in angiogenesis-related pathways. Additionally, positive correlations were found between ITGA6 expression and pro-tumorigenic immune cells, but not with anti-tumorigenic immune cells. Our study elucidates the potential of ITGA6 as a blood-based marker for HCC early detection and diagnosis and its complex interplay with the tumor microenvironment. Further research may lead to novel strategies for HCC management and patient care.