Molecular Function Validation and Prognostic Value Analysis of the Cuproptosis-Related Gene Ferredoxin 1 in Colon Cancer

Abstract

Background Cuproptosis is the most recently discovered form of regulated cell death (RCD) induced by intracellular copper. Growing evidence has indicated that cuproptosis plays a considerable role in tumorigenesis among various cancers. However, the role of cuproptosis in the development of colon cancer (CC) and its prognostic value remains to be investigated. Methods Five independent cohorts with CC were included in this study. Comprehensive bioinformatics analyses were used to explore the expression, molecular function, and prognostic value of the pivotal regulator of cuproptosis, ferredoxin 1 (FDX1). Correlation analyses and least absolute shrinkage and selection operation (LASSO) regression analyses were utilized to screen the optimal combination of cuproptosis-related genes for constructing a Cox proportional hazards model, and the cuproptosis-related risk score (CRRS) was calculated to stratify CC patients in prognosis. The immunology, tumor stemness index, and drug sensitivity of the CRRS-based subgroups were also investigated. Moreover, the expression and biological functions of FDX1 were validated in vitro. Results Results showed that FDX1 was significantly downregulated in CC and its lower expression indicated poorer outcomes. Seven cuproptosis-associated genes were selected to construct the prognostic model. CRRS displayed good performance in predicting prognosis compared with clinical features. Moreover, CRRS could significantly enhance the prognostic prediction precision of the classic tumor, nodes, and metastases (TNM) staging system. The high-CRRS group showed an obvious immunosuppressive microenvironment and a lower stemness index compared with the low-CRRS group. The difference in FDX1 expression between CC and normal tissues was verified in vitro. Overexpression of FDX1 promoted cell death and inhibited cell proliferation and migration. Conclusions Our results suggest that CRRS can function as a good prognostic indicator for CC patients and may help guide treatment management. Our findings provide new insights into cuproptosis-targeted therapies for CC patients.