Single-cell and bulk transcriptomic analyses reveal ITGA5-driven epithelial-mesenchymal transition and metabolic...

Thyroid cancer (THCA) progression and poor outcomes are driven by poorly understood molecular pathways. Integrin α5 (ITGA5) has been implicated in tumor aggressiveness, but its specific functions in THCA remain unknown.

ITGA5 expression and survival associations were analyzed through TCGA pan-cancer and THCA RNA-seq data. WGCNA was used to identify ITGA5-related gene modules, which were functionally analyzed by GO and pathway analysis. In vitro, ITGA5 was silenced in BCPAP and 8505C cells to assess proliferation capacity, colony formation, migration, invasion, and mitochondrial function.

ITGA5 expression was upregulated in THCA tumor tissue and associated with poor overall survival. WGCNA identified a gene module associated with ITGA5 high-expressed patients were correlated with epithelial-mesenchymal transition and extracellular matrix remodeling. Single-cell RNA sequencing demonstrated that this module was specifically enriched in malignant epithelial cells. Functional enrichment further showed that cancer cells with high module scores exhibited an enhanced oxidative stress response. Using ESTIMATE and immune deconvolution, we found that ITGA5-high tumors exhibited higher stromal content but reduced immune infiltration, including fewer CD8⁺ T cells, NK cells, and B-cell subsets. In vitro, ITGA5 silencing significantly attenuated THCA cell proliferation, motility, invasion, mitochondrial ROS, and focal adhesion signaling.

ITGA5 promotes aggressive phenotypes in THCA through activation of epithelial-mesenchymal transition and tumor microenvironment remodeling. These findings provide a mechanistic basis for targeting ITGA5 in THCA.