Establishment and external verification of an oxidative stress-related gene signature to predict clinical outcomes and therapeutic responses of colorectal cancer

Abstract

Objective: Accumulated evidence highlights the biological significance of oxidative stress in tumorigenicity and progression of colorectal cancer (CRC). Our study aimed to establish a reliable oxidative stress-related signature to predict patients’ clinical outcomes and therapeutic responses.Methods: Transcriptome profiles and clinical features of CRC patients were retrospectively analyzed from public datasets. LASSO analysis was used to construct an oxidative stress-related signature to predict overall survival, disease-free survival, disease-specific survival, and progression-free survival. Additionally, antitumor immunity, drug sensitivity, signaling pathways, and molecular subtypes were analyzed between different risk subsets through TIP, CIBERSORT, oncoPredict, etc. approaches. The genes in the signature were experimentally verified in the human colorectal mucosal cell line (FHC) along with CRC cell lines (SW-480 and HCT-116) through RT-qPCR or Western blot.Results: An oxidative stress-related signature was established, composed of ACOX1, CPT2, NAT2, NRG1, PPARGC1A, CDKN2A, CRYAB, NGFR, and UCN. The signature displayed an excellent capacity for survival prediction and was linked to worse clinicopathological features. Moreover, the signature correlated with antitumor immunity, drug sensitivity, and CRC-related pathways. Among molecular subtypes, the CSC subtype had the highest risk score. Experiments demonstrated that CDKN2A and UCN were up-regulated and ACOX1, CPT2, NAT2, NRG1, PPARGC1A, CRYAB, and NGFR were down-regulated in CRC than normal cells. In H2O2-induced CRC cells, their expression was notably altered.Conclusion: Altogether, our findings constructed an oxidative stress-related signature that can predict survival outcomes and therapeutic response in CRC patients, thus potentially assisting prognosis prediction and adjuvant therapy decisions.

The exploration of mitochondrial‐related features helps to reveal the prognosis and immunotherapy methods of colorectal cancer

“…However, the link between increased PPARGC1A expression and a favorable prognosis in clear cell renal cell carcinoma remains contentious 83 . The mutation of PPARGC1A has been shown to contribute to CRC susceptibility 84 and can serve as a negative biomarker for CRC 85,86 . EF hand domain family member D1 (EFHD1) is a calcium‐binding protein located in the inner mitochondrial membrane 87 .…”

“…83 The mutation of PPARGC1A has been shown to contribute to CRC susceptibility 84 and can serve as a negative biomarker for CRC. 85 , 86 EF hand domain family member D1 (EFHD1) is a calcium‐binding protein located in the inner mitochondrial membrane. 87 The combined detection of EFHD1 and PPP1R3C methylation in plasma DNA tests of CRC patients can show high sensitivity and specificity, 88 this might aid in the early detection of CRC patients.…”

Synthesis of Bis-Chalcones and Evaluation of Its Effect on Peroxide-Induced Cell Death and Lipopolysaccharide-Induced Cytokine Production

“…In the Indian population, the incidence of CRC is much lower with an age-standardized ratio of 7.2 per 100,000; however, it should be noted that the country accounts for a significantly lower 5-year survival rate in CRC with respect to global standards [4,5]. Oxidative stress is a key event in the onset and progression of intestinal disorders including colorectal cancers [6,7]. The initial events of oxidative stress begin with the imbalance in the production of reactive radical moieties in the cells and also with the scavenging of these reactive molecules [8].…”