Abstract
Solute carrier family 25 (SLC25) encodes transport proteins at the inner mitochondrial membrane and functions as carriers for metabolites. Although SLC25 genetic variants correlate with human metabolic diseases, their roles in colon cancer remain unknown. Cases of colon cancer were retrieved from The Cancer Genome Atlas, and the transcriptionally differentially expressed members (DEMs) of SLC25 were identified. DNA level alterations, clinicopathological characteristics, and clinical survival were also investigated. A risk score model based on the DEMs was constructed to further evaluate their prognostic values in a clinical setting. The results were preliminarily validated using bioinformatic analysis of datasets from the Gene Expression Omnibus, immunohistochemical evaluations in clinical specimens, and functional experiments in colon cancer-derived cell lines. Thirty-seven DEMs were identified among 53 members of SLC25. Eight of 37 DEMs were introduced into a risk score model using integrated LASSO regression and multivariate Cox regression. Validated by GSE395282 and GSE175356, DEMs with high-risk scores were associated with the phenotypes of increasing tumor immune infiltration and decreasing glycolysis and apoptosis contents. SLC25A5 was downregulated in cancer, and its upregulation was related to better overall survival in patients from public datasets and in clinical cases. High SLC25A5 expression was an independent prognostic factor for 79 patients after surgical treatment. A negative correlation between CD8 and SLC25A5 was determined in specimens from 106 patients with advanced colon cancer. SLC25A5 attenuated cell proliferation, upregulated the expression of programmed cell death-related signatures, and exerted its biological function by inhibiting the MAPK signaling pathway. Our study reveals that mitochondrial SLC25 has prognostic value in patients with colon cancer. The bioinformatic analyses by following verification in situ and in vitro provide direction for further functional and mechanistic studies on the identified member of SLC25.
Highlights
Colorectal cancer (CRC) is common in the West and East and has relatively high morbidity and mortality [1, 2]
We identified 177 items for terms of biological process (BP), 69 items for terms of cellular component (CC), 38 items for terms of molecular function (MF), and 8 items for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways based on the differentially expressed genes (DEGs) determined by the expression of SLC25A5, while we identified 131 items for terms of BP, 24 items for terms of CC, 28 items for terms of MF, and 4 items for KEGG pathways based on the DEGs determined by the expression of SLC25A24
Validation of the gene set enrichment analysis (GSEA) results of SLC25A5 with respect to glycolysis, lipid metabolism, and cancer-related cell signaling pathways Based on the previous GSEA results, we found that glycolysis- and adipogenesis-related enzymes, such as ENO-1, EBP, IDI-1, HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase), and MVD, were differentially expressed when SLC25A5 (Fig. 8A) and SLC25A24 (Fig. S6E) were upregulated in HCT116 cells
Summary
Colorectal cancer (CRC) is common in the West and East and has relatively high morbidity and mortality [1, 2]. Since energy metabolism reprogramming, characterized by aerobic glycolysis and mitochondrial oxidative phosphorylation dysfunction, is a hallmark of cancer, understanding the novel molecular mechanism regulating mitochondrial metabolism in tumorigenesis, tumor growth, metastasis, and drug tolerance is critical for antitumor therapy development [3]. Mitochondrial membrane transport proteins are located in the inner mitochondrial membrane and act as carriers for metabolic substrates (Fig. 1A). Horimoto reported that SLC25A8 is upregulated in colon cancer and is related to tumor differentiation [6]. Kuai found that SLC25A14 represses the increase in H2O2 products resulting from mitochondrial dysfunction in a feedback mechanism in colon cancer [7]. We previously demonstrated that SLC25A18 is a prognostic biomarker for patients with colon cancer and can suppress cell glycolysis and proliferation by suppressing Wnt/β-catenin cascades [8]
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