Screening of key genes related to ferroptosis and a molecular interaction network analysis in colorectal cancer using machine learning and bioinformatics

Abstract

Background This study sought to identify the key genes and molecular interactions related to ferroptosis in colorectal cancer (CRC) using machine-learning and bioinformatics analyses. Methods The Gene Expression Omnibus (National Institutes of Health, US) datasets for CRC were downloaded from the National Center for Biotechnology Information (NCBI) ( https://www.ncbi.nlm.nih.gov/ ). The 291 ferroptosis genes were downloaded and screened from the FerrDb ( http://www.zhounan.org/ferrdb ) and GeneCards ( https://www.genecards.org/ ) databases. The least absolute shrinkage and selection operator regression model and support vector machine model were constructed to identify the different ferroptosis-related hub genes. The immune infiltrates were identified and a survival curve analysis was conducted. Results We identified 11 ferroptosis-related differentially expressed genes (DEGs) from the COADREAD (Colon and Rectal Cancer) dataset. We found that angiopoietin-related protein 7 ( ANGPTL7 ) gene expression was positively correlated to both the neuroglobin ( NGB ) (r=0.678) and ceruloplasmin (CP) (r=0.454) genes but was negatively correlated with transferrin receptor 2 ( TFR2 ) expression (r=–0.426). In addition, TFR2 gene expression was positively correlated with the arachidonate lipoxygenase 3 ( ALOXE3 ) (r=0.452) and carbonic anhydrase 9 ( CA9 ) (r=0.411) genes. A total of 4 hub genes were identified by the machine-learning analysis [i.e., NADPH oxidase 4 ( NOX4 ), TFR2, ALOXE3 , and CA9 ]. The expression of the NOX4 gene was significantly positively correlated with neutrophil (r=0.543) and M0 macrophage (r=0.422) infiltration. In addition, a positive correlation between ALOXE3 and activated natural-killer cells (r=0.356) was found. Conversely, the NOX4, TFR2 , and CA9 genes were negatively correlated with the resting mast cells. A strong negative correlation was observed between NOX4 and CD160 antigen ( CD160 ) expression; however, a significant positive correlation was observed between NOX4 and transforming growth factor beta receptor 1 ( TGFBR1 ) expression (r=0.397). The patients had a more favorable prognosis when the NOX4 expression levels were relatively low. Conclusions Our study identified 4 ferroptosis-related DEGs in CRC (i.e., NOX4, TFR2 , ALOXE3 , and CA9 ), and fur...

Nutritional Modulation of Hepcidin in the Treatment of Various Anemic States

“…NOX4 Oxidase is another link between hepcidin and ferroptosis (Figure 2). Studies on differentially expressed genes (DEGs) reported that the NOX4 gene is strongly related to ferroptosis in colorectal cancer [85] and in gastric adenocarcinoma [86]. The increase in the expression and activity of NOX4 increases oxidative stress [87], and this promotes lipid peroxidation.…”

Co-vulnerabilities of inhibiting carbonic anhydrase IX in ferroptosis-mediated tumor cell death

“…The CA9 gene was among four “hub” ferroptosis-related genes identified using machine learning and bioinformatics approaches to establish key genes and molecular interactions associated with ferroptosis in colorectal cancer ( Xue et al, 2023 ). Interestingly, expression of CA9 was positively correlated with expression of transferrin receptor 2 (TFR2) in colorectal cancer, suggesting an association between CA9 and iron transport, which is a key process associated with ferroptosis ( Xue et al, 2023 ). Hypoxia-mediated upregulation of CA9 expression and increased catalytic iron (Fe 2+ ) has also been observed in malignant mesothelioma ( Li et al, 2019 ).…”

“…Further studies have strengthened the link between CAIX and ferroptosis. The CA9 gene was among four "hub" ferroptosis-related genes identified using machine learning and bioinformatics approaches to establish key genes and molecular interactions associated with ferroptosis in colorectal cancer (Xue et al, 2023). Interestingly, expression of CA9 was positively correlated with expression of transferrin receptor 2 (TFR2) in colorectal cancer, FIGURE 1 CAIX regulates tumour cell vulnerability to ferroptosis.…”

“…Frontiers in Molecular Biosciences frontiersin.org suggesting an association between CA9 and iron transport, which is a key process associated with ferroptosis (Xue et al, 2023). Hypoxiamediated upregulation of CA9 expression and increased catalytic iron (Fe 2+ ) has also been observed in malignant mesothelioma (Li et al, 2019).…”