Integrative analysis of SLFN11-related DEGs reveals novel biomarkers for cisplatin sensitivity and immune modulation in colorectal cancer

BACKGROUND: Cisplatin is a widely used chemotherapy drug, but resistance mechanisms, including the role of SLFN11, pose significant challenges in colorectal cancer (CRC) treatment, with only 15-20% of patients showing objective responses. METHODS: We conducted differential gene expression analysis using datasets GSE181094, GSE179896, and GSE231559, alongside TCGA-COAD and TCGA-READ datasets. DEGs were identified using DESeq2, Limma, and edgeR, followed by protein-protein interaction network analysis with STRING, and functional enrichment analysis via KEGG, GO, and GSEA. Mendelian randomization (MR) analysis was performed using the TwoSampleMR package with robust instrumental variable validation, and single-cell RNA sequencing data was analyzed using Seurat and SingleR to examine cell-type specific expression patterns. RESULTS: Our analysis identified several DEGs, including FOXL1 and GPC4, associated with cisplatin sensitivity in SLFN11 knockout cell lines. MR analysis revealed SLC46A3 as a significant gene related to CRC, showing a causal relationship (β=-0.2935, p = 0.0308). Single-cell RNA sequencing demonstrated high expression of SLFN11 in granulocyte-monocyte progenitor and common myeloid progenitor cells in adjacent normal tissues, with reduced expression in cancerous tissues. These findings highlight the significant impact of SLFN11 on gene expression and its potential as a biomarker for cisplatin sensitivity. CONCLUSION: SLFN11 plays a critical role in modulating cisplatin sensitivity in CRC, with implications for personalized cancer therapy. These findings establish SLFN11 as a potential biomarker for personalizing cisplatin-based therapies in CRC patients, potentially improving response rates and clinical outcomes.