FNDC5 and ACOX1 as Biomarkers of Peroxisomal Activity with Contrast Outcomes in Colon Adenocarcinoma
Abstract Background Colorectal cancer progression and immune evasion are closely linked to mitochondrial and peroxisomal metabolic reprogramming, yet the role of peroxisomes remains underexplored. Objective This study aims to investigate the contribution of peroxisomal metabolism to colorectal cance...
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| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-07-01
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| Series: | Biological Procedures Online |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12575-025-00289-y |
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| Summary: | Abstract Background Colorectal cancer progression and immune evasion are closely linked to mitochondrial and peroxisomal metabolic reprogramming, yet the role of peroxisomes remains underexplored. Objective This study aims to investigate the contribution of peroxisomal metabolism to colorectal cancer biology and identify potential metabolic vulnerabilities for therapeutic targeting. Methods Transcriptomic and clinical data from TCGA-COAD and GEO (GSE39582) served as training and validation cohorts. Of 106 shared peroxisome-related genes (PRGs), seven were identified via univariate Cox and refined using LASSO regression to build a prognostic model. Tumor microenvironment features were assessed using ESTIMATE, MCP-counter, and CIBERSORT. Single-cell RNA-seq data (TISCH; EMTAB8107) were used to examine cell-type-specific PRG expression. For experimental validation, qPCR and Western blotting assessed gene expression in colon cancer cell lines. FNDC5 was silenced via siRNA in SW480 and HCT116 cells, followed by CCK-8 and colony formation assays. IHC evaluated protein levels in clinical specimens. Analyses were conducted in R. Results A seven-gene PRG risk signature was constructed, including four risk-associated genes: ABCD1 (ATP Binding Cassette Subfamily D Member 1), FNDC5 (Fibronectin Type III Domain Containing 5), HAO2 (Hydroxyacid Oxidase 2), and PEX5L (Peroxisomal Biogenesis Factor 5 Like), as well as three protective genes: ABCD3 (ATP Binding Cassette Subfamily D Member 3), ACOX1 (Acyl-CoA Oxidase 1), and NOS2 (Nitric Oxide Synthase 2). COAD patients were stratified into high- and low-risk groups based on PRG risk signature, with the high-risk group showing significantly worse survival in both cohorts. The high-risk group was linked to advanced stage, higher MSI, CMS4 subtype enrichment, distinct mutation patterns, and increased genome integrity pathway mutations (79% vs. 66%). It also showed greater stromal infiltration, including fibroblasts, endothelial cells, and monocytes. Single-cell RNA-seq confirmed differential PRG expression across tumor, stromal, and immune cells. Among the PRG risk genes, FNDC5 and ACOX1 were identified as key biomarkers. FNDC5 was markedly upregulated in cancer cells, and western blot confirmed its elevated protein levels (p < 0.001). Functional assays following FNDC5 knockdown in SW480 and HCT116 cells demonstrated efficient silencing by qPCR and western blot, significantly reduced cell viability (CCK-8 assay), and impaired colony formation, supporting its role as a potential oncogene in colorectal cancer. Conclusion FNDC5 and ACOX1 were identified as key peroxisome-related biomarkers with opposing roles in colon adenocarcinoma, highlighting peroxisomal metabolism’s contribution to tumor progression. FNDC5 promotes tumor growth, while ACOX1 appears protective, offering potential targets for therapeutic intervention. |
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| ISSN: | 1480-9222 |