Association of CDKN2A overexpression with poor prognosis, radioresistance, and immunosuppression in colorectal cancer.

BACKGROUNDIn colorectal cancer (CRC), dysregulated cyclin-dependent kinase inhibitor 2A (CDKN2A) contributes to disease progression. This investigation sought to explore the link between CDKN2A expression and the effectiveness of radiotherapy in CRC, and to investigate the underlying mechanisms.

METHODSTranscriptomic and clinical datasets were procured from the Cancer Genome Atlas and Gene Expression Omnibus databases. Immune cell infiltration was assessed using xCell, CIBERSORT, and EPIC methods. Biological mechanisms were investigated through the utilization of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. HCT 116 cells were used for in vitro and in vivo experiments.

RESULTSBulk and single-cell transcriptome analyses and immunohistochemistry consistently revealed elevated CDKN2A expression in tumor specimens from patients with CRC. Patients with tumors that were nonresponsive to neoadjuvant chemoradiotherapy had significantly higher CDKN2A expression than those of responders (P = 0.039). CDKN2A knockdown in tumor led to a marked decrease in the proliferation, invasion, and migration capabilities, and this effect was enhanced by combined X-ray irradiation. Elevated CDKN2A expression was linked to markedly worse survival. In the tumor immune microenvironment, CDKN2A expression was negatively linked to CD8+ cell infiltration and positively correlated with the levels of immunosuppressive factors. Functional enrichment analysis indicated that elevated CDKN2A expression is linked to transcriptional regulation, amino acid metabolism, protein folding, and the TGF-β signaling pathway.

CONCLUSIONIn CRC, CDKN2A overexpression is associated with unfavorable responses to radiotherapy, an immunosuppressive tumor microenvironment, and poor prognosis. Suppression of CDKN2A expression could potentially improve therapeutic outcomes in CRC patients. More experimental and clinical studies are still needed to verify and further distinguish the similarities and differences between colon cancer and rectal cancer.