Identification of key genes involved in tumor immune cell 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 cell infiltration. Methods A cetuximab-resistant CACO2 cellular model was established, and its transcriptome variations were detected by microarray. Meanwhile, public data from the Gene Expression Omnibus and The Cancer Genome Atlas (TCGA) database were downloaded. Integrated bioinformatics analysis was applied to detect differentially expressed genes (DEGs) between the cetuximab-resistant and the cetuximab-sensitive groups. Then, we investigated correlations between DEGs and immune cell infiltration. The DEGs from bioinformatics analysis were further validated in vitro and in clinical samples. Results We identified 732 upregulated and 1259 downregulated DEGs in the induced cellular model. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, along with Gene Set Enrichment Analysis and Gene Set Variation Analysis, indicated the functions of the DEGs. Together with GSE59857 and GSE5841, 12 common DEGs (SATB-2, AKR1B10, ADH1A, ADH1C, MYB, ATP10B, CDX-2, FAR2, EPHB2, SLC26A3, ORP-1, VAV3) were identified and their predictive values of cetuximab treatment were validated in GSE56386. In online Genomics of Drug Sensitivity in Cancer (GDSC) database, nine of twelve DEGs were recognized in the protein-protein (PPI) network. Based on the transcriptome profiles of CRC samples in TCGA and using Tumor Immune Estimation Resource Version 2.0, we bioinformatically determined that SATB-2, ORP-1, MYB, and CDX-2 expressions were associated with intensive infiltration of B cell, CD4+ T cell, CD8+ T cell and macrophage, which was then validated the correlation in clinical samples by immunohistochemistry. We found that SATB-2, ORP-1, MYB, and CDX-2 were downregulated in vitro with cetuximab treatment. Clinically, patients with advanced CRC and high ORP-1 expression exhibited a longer progression-free survival time when they were treated with anti-EGFR therapy than those with low ORP-1 expression. Conclusions SATB-2, ORP-1, MYB, and CDX-2 were related to cetuximab sensitivity as well as enhanced tumor immune cell infiltration in patients with CRC.

Construction of a Two-Gene Immunogenomic-Related Prognostic Signature in Lung Squamous Cell Carcinoma

“…In human glioma cells, CSF2 can promote cell growth and invasion (Sielska et al, 2020). In addition, the expression of these IRGs can be regulated by the transcription factors MYB, SP1, and SP3, which are related to tumor immunity (Beug et al, 2019;Liang et al, 2021;Yu et al, 2021). These findings imply that the identified IRGs or TFs may be therapeutic targets or novel biomarkers for LUSC.…”

Emerging role of MYB transcription factors in cancer drug resistance

“…The upregulation of MYBL2 as a key MAG in lung adenocarcinomas was associated with low response to erlotinib [86] . The monoclonal anti-EGFR antibody cetuximab is approved for the therapy of metastatic CRC and head-and-neck squamous cell carcinoma [116] . MYB was strongly downregulated in cetuximab-resistant CRC cells, while MYB expression was associated with cetuximab sensitivity and increased tumor immune cell infiltration [117] .…”

“…The monoclonal anti-EGFR antibody cetuximab is approved for the therapy of metastatic CRC and head-and-neck squamous cell carcinoma [ 116 ] . MYB was strongly downregulated in cetuximab-resistant CRC cells, while MYB expression was associated with cetuximab sensitivity and increased tumor immune cell infiltration [ 117 ] . In contrast to that, upregulated MYBL2 was correlated with cetuximab resistance in NSCLC cells, which was mediated by Src-family kinase Yes- and Lin-promoted EGFR nuclear translocation and the binding of nuclear EGFR complexes to the MYBL2 promoter [ 118 ] .…”