Novel characterization discoveries of ferroptosis-associated molecules in COAD microenvironment based TCGA data

Salem Baldi; Yun He; Igor Ivanov; Yaping Sun; Wei Feng; Moath Refat; Shadi A D Mohammed; Salah Adlat; Zixuan Tian; Yi Wang; Yaping Gao; Hui Tian

doi:10.3389/fmolb.2022.1102735

Novel characterization discoveries of ferroptosis-associated molecules in COAD microenvironment based TCGA data

Front Mol Biosci. 2022 Dec 13:9:1102735. doi: 10.3389/fmolb.2022.1102735. eCollection 2022.

Authors

Salem Baldi¹, Yun He¹, Igor Ivanov¹, Yaping Sun², Wei Feng¹, Moath Refat³, Shadi A D Mohammed⁴, Salah Adlat⁵, Zixuan Tian¹, Yi Wang¹, Yaping Gao², Hui Tian¹

Affiliations

¹ Research Center of Molecular Diagnostics and Sequencing, Axbio Biotechnology (Shenzhen) Co., Ltd., Shenzhen, China.
² Research Center of Molecular Diagnostics and Sequencing, Research Institute of Tsinghua University in Shenzhen, Shenzhen, China.
³ Department of Biochemistry and Molecular Biology, The Key Laboratory of Environment and Genes Related to Disease of Ministry of Education, Health Science Center, Xi'an Jiaotong University, Xi'an, China.
⁴ Graduate School of Heilongjiang University of Chinese Medicine, Harbin, China.
⁵ Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States.

Abstract

Background and Objective: One of the most recent forms of programmed cell death, ferroptosis, is crucial in tumorigenesis. Ferroptosis is characterized by iron-dependent oxidative destruction of cellular membranes following the antioxidant system's failure. However, it is unknown whether ferroptosis-related genes (FRGs) are associated with colon adenocarcinoma (COAD) metastasis, immune cell infiltration, and oxidative stress in COAD. The current study concentrated on FRGs expression in colon cancer metastasis, their relationship to immune cell infiltration (ICI), and potential pathological pathways in COAD. Methods and Results: Clinical information and mRNA expression patterns for patients with COAD metastasis were obtained from the public TCGA database. Patients with low mRNA levels showed good overall survival than patients with high mRNA levels. The genomic-clinicopathologic nomogram was subsequently created by combining risk score and clinicopathological features. Absolute Shrinkage and Selection Operator have shown a 4 gene signature that can stratify cancer patients into high-risk versus low-risk. These four FRGs were found to be significantly linked to the overall survival of COAD patients and predicted high risk score. Next, age, stage, and PTNM were combined in univariate and multivariate cox regression models to perform a filtering procedure. The receiver operating characteristic (ROC) and calibration curves indicated that constructed signature model exhibited high prediction accuracy and clinical relevance in COAD. ARID3A showed a strong negative correlation with a wide range of immune tumour-infiltrating cells in COAD microenvironment. According to the single sample gene set enrichment analysis (ssGSEA) results, FRGs are involved in variety of pathological pathways including PI3K-AKT-mTOR pathway, reactive oxygen species (ROS) pathway, response to hypoxia pathway, and other inflammation related pathways. Moreover, dysregulation of FRGs in COAD patients showed a significance correlation with wide range of miRNAs and transcription factors (TFs). Conclusion: We identified new diagnostic biomarkers and established prognostic models for ferroptosis related programmed cell death in COAD metastasis. FRGs may improve tumor cell survival by activating the TGFB pathway, which can stimulate ROS production, accelerates ECM breakdown, and promote tumor progression and invasion. Genes implicated in ferroptosis, as revealed by the Kaplan Meier and a genomic-clinicopathologic nomogram, are potential therapeutic targets and prognosis indications for metastasis COAD patients.

Keywords: COAD microenvironment; TCGA; ferroptosis; immune cell infiltration; metastasis.