Abstract
BackgroundLeft- and right-sided colorectal cancer (LCRC, RCRC) are significantly different in epidemiology and clinical manifestations and have altered outcomes. However, as a hot tumor prognostic marker, the role of ferroptosis-related genes (FRGs) in LCRC and RCRC is unknown.MethodsFrom The Cancer Genome Atlas (TCGA) database, we downloaded the expression profiles of CRC patients. A “DESeq2” package was performed to compare the differentially expressed genes (DEGs) of LCRC and RCRC. FRGs were identified using the FerrDb. The prognostic value of differentially expressed FRG (DE-FRG) in left- and right-CRC was assessed separately by Cox regression analysis. Subsequently, functional enrichment analysis, ESTIMATE, and single sample Gene Set Enrichment Analysis (ssGSEA) were performed based on LCRC and RCRC samples to reveal the potential function of FRGs-related risk signatures. The differential expression of FRGs in tumor tissues and adjacent normal tissues were verified by Western blot. The differential expression and prognosis in LCC and RCC were verified by immunohistochemistry.ResultsBased on the identified 14 DE-FRGs, the LCRC prognostic model consisted of NOS2 and IFNG; NOS2 and ALOXE established the prognostic signature that could distinguish RCRC outcomes. In the functional analysis, the DEGs (high risk vs. low risk) of the LCRC and RCRC were significantly enriched in the immune- and lipid-related terms and pathways. ESTIMATE and ssGSEA suggested that these FRGs-related risk signatures were affiliated with the infiltration of immune cell subtypes. Western blotting results showed that NOS2 and ALOXE3 were significantly highly expressed in cancer, and the difference was statistically significant (P < 0.05). Immunohistochemical results showed that ALOXE3 was highly expressed in RCC, and those with high expression had a worse prognosis, while NOS2 gene had an effect on the prognosis of both LCC and RCC.ConclusionThis study constructed a potential prognostic model of LCRC and RCRC, respectively. We also identified the crucial pathways that contribute to elucidating the pathogenesis of CRC.
Highlights
Colorectal cancer (CRC) is the third most common cancer worldwide and a fatal disease
Based on the identified 14 DE-ferroptosis-related genes (FRGs), the left-sided colorectal cancer (LCRC) prognostic model consisted of NOS2 and Interferon gamma (IFNG); NOS2 and ALOXE established the prognostic signature that could distinguish right-sided colorectal cancer (RCRC) outcomes
Based on the The Cancer Genome Atlas (TCGA)-CRC database, we performed univariate Cox regression analysis in the LCRC-training set and RCRCtraining set for the 14 Differentially expressed ferroptosis-related genes (DE-FRGs) mentioned above to investigate whether these genes were associated with overall survival (OS) in LCRC/RCRC patients (P < 0.2)
Summary
Colorectal cancer (CRC) is the third most common cancer worldwide and a fatal disease. The mortality rate of CRC has been declining since 1990, it still remains at approximately 1.7-1.9% [1]. According to the origin of the lesion, the disease can be divided into right-sided colorectal cancer (RCRC) and left-sided colorectal cancer (LCRC) [2]. RCRC derives from the midgut including the cecum, ascending colon, and transverse colon. LCRC derives from the hindgut mainly composed of splenic flexure, rectum, descending colon and sigmoid colon [3]. The difference between LCRC and RCRC has attracted increasing attention. Left- and right-sided colorectal cancer (LCRC, RCRC) are significantly different in epidemiology and clinical manifestations and have altered outcomes. As a hot tumor prognostic marker, the role of ferroptosis-related genes (FRGs) in LCRC and RCRC is unknown
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