THBS3 Functions as a Novel Biomarker for Prognosis and Immunotherapeutic Response in Colorectal Cancer: An Integrative Analysis and Validation of the Thrombospondin Gene Family.

[BACKGROUND] The THBS gene family plays key functions in various diseases; however, its specific roles in colorectal cancer (CRC) have not been systematically characterized.

[METHODS] Multi-omics data and online databases were used to analyze the mRNA expression levels of the THBS gene family in CRC and their correlations with clinicopathological features and survival. This analysis identified THBS3 as a potential oncogene closely linked with CRC progression. Then, the relationship between THBS3 expression and the immune landscape was assessed. Single-cell RNA sequencing analyzed THBS3 distribution in CRC subtypes. Additionally, GO, KEGG, and GSEA enrichment analyses investigated the mechanisms of THBS3 in CRC. Molecular docking identified anticancer compounds with high affinity for THBS3. Lastly, in vitro experiments examined THBS3's function in CRC.

[RESULTS] THBS3 was significantly upregulated in CRC and correlated with poor prognosis. Elevated THBS3 correlated with increased infiltration of M2 macrophages and regulatory T cells (Treg cells), as well as higher expression of immune checkpoint molecules, suggesting its role in shaping an immunosuppressive microenvironment. THBS3 promoted CRC cell proliferation and metastasis, through activation of the PI3K-AKT and EMT pathways.

[CONCLUSION] THBS3 facilitates the progression of CRC and may serve as a novel prognostic biomarker and therapeutic target.