Unveiling VARS1: a key driver of colorectal cancer progression and immune modulation

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Valyl-tRNA synthetase 1 (VARS1), an aminoacyl-tRNA synthetase, has been implicated in various cancers, but its role in CRC remains unclear. This study investigated the expression pattern, clinical significance, biological functions, and potential molecular associations of VARS1 in CRC.

VARS1 expression was analyzed in CRC tissues using TCGA/GEO databases, immunohistochemistry, and Western blotting. Prognostic models were built via Cox regression and nomograms. In vitro, VARS1 was knocked down in CRC cell lines to assess proliferation (CCK-8, colony formation), migration/invasion (wound healing, Transwell), and EMT markers. Immune infiltration was evaluated with TIMER/CIBERSORT, single-cell analysis via Seurat/CellChat, drug sensitivity via GDSC2, and pathways via GO/KEGG/GSEA.

VARS1 was overexpressed in CRC, correlating with poor survival as an independent risk factor. Knockdown suppressed cell proliferation, migration, invasion, accompanied by changes in EMT-related markers. High VARS1 expression was associated with reduced CD8⁺ T-cell infiltration and altered predicted cell-cell communication patterns within the tumor microenvironment. VARS1 was associated with altered predicted chemotherapy sensitivity. GSEA and phosphorylation analyses suggested a potential association between VARS1 and JAK/STAT pathway activity.

Our findings suggest that VARS1 is associated with malignant phenotypes, immune-related features, and chemotherapy response in CRC, and may serve as a potential prognostic biomarker.