Identification of Key Genes Involved in Tumor Immune Infiltration and Cetuximab Resistance in Colorectal Cancer

Abstract

Background: The anti-epidermal growth factor receptor (EGFR) antibody introduces adaptable variations to the transcriptome and triggers tumor immune infiltration, resulting in colorectal cancer (CRC) treatment resistance. We intended to identify genes that play essential roles in cetuximab resistance and tumor immune infiltration. Methods: A cetuximab-resistant CACO2 cellular model was established, while public data from The Cancer Genome Atlas database and Gene Expression Omnibus were downloaded. Integrated bioinformatics analysis was applied to detect differentially expressed genes (DEGs) between the cetuximab-resistant and the cetuximab-sensitive groups. Then we investigate correlations between DEGs and immune infiltration. Findings: Results from bioinformatics analysis were further validated in vitro and clinical samples. We identified 732 upregulated and 1259 downregulated DEGs. Among them, SATB-2, ORP-1, MYB, and CDX-2 expressions were correlated with intensive tumor immune infiltration. ORP-1, MYB, and CDX-2 were downregulated after the cetuximab treatment in colorectal cell lines. Patients with high ORP-1 expression exhibited an optimal response to anti-EGFR therapy. Interpretation: In conclusion, SATB-2, ORP-1, MYB, and CDX-2 enhanced tumor immune infiltration and cetuximab sensitivity in CRC. Funding Statement: Outstanding Youth Foundation of Zhongshan Hospital (No. 2019ZSYQ21), CSCO-Youth 37 Innovation Research Fund (Y-young2019-057), and National Natural Science Foundation of China 38 (81602038, 81772511 and 81900482). Declaration of Interests: The authors have no conflicts of interest to declare. Ethics Approval Statement: Patients signed informed consent documents, and the ethics committee of Zhongshan Hospital approved the study.