Pan-cancer investigation identifies ARL4A as a prospective therapeutic indicator for thyroid cancer

ADP-ribosylation factor-like 4 A (ARL4A), a small GTPase involved in cytoskeletal dynamics and signal transduction, exhibits dysregulated expression in various cancers, yet its comprehensive role across tumor types, particularly in thyroid carcinoma (THCA), remains underexplored. This study aimed to perform a systematic pan-cancer analysis of ARL4A to elucidate its expression patterns, prognostic implications, genetic and epigenetic alterations, immune correlations, drug sensitivity, and functional contributions to THCA progression.

Leveraging multi-omics data from TCGA and tools including TIMER2.0, GEPIA2, UALCAN, cBioPortal, and LinkedOmics, we evaluated ARL4A across 33 cancer types. Functional validation was conducted by overexpressing ARL4A in THCA cell lines (BCPAP and KTC-1), with assessments via Western blotting, CCK-8 proliferation assays, wound healing, and Transwell migration assays.

ARL4A mRNA levels were significantly reduced in tumors such as THCA, correlating with early stages in some cancers but poor overall survival in THCA, adrenocortical carcinoma, and bladder cancer. Genetic amplifications predominated, alongside promoter hypomethylation in multiple malignancies. ARL4A expression inversely correlated with CD8 + T cells and other antitumor infiltrates while positively associating with myeloid-derived suppressor cells and immunosuppressive chemokines. Drug sensitivity analysis revealed negative correlations with HSP90 inhibitors. In THCA cells, ARL4A overexpression enhanced proliferation, migration, and epithelial-mesenchymal transition markers (N-cadherin and Vimentin).

These results establish ARL4A as an oncogenic promoter in THCA through modulation of proliferation, migration, and immunosuppressive microenvironments, positioning it as a promising prognostic biomarker and therapeutic target for precision oncology.