Abstract
Background: Esophageal squamous cell carcinoma (ESCC) is a gastrointestinal malignancy with a poor prognosis. Although studies have shown metabolic reprogramming to be linked to ESCC development, no prognostic metabolic biomarkers or potential therapeutic metabolic targets have been identified.Method: The present study investigated some circulating metabolites associated with overall survival in 276 curatively resected ESCC patients using liquid chromatography/mass spectrometry metabolomics and Kaplan-Meier analysis. Tissue metabolomic analysis of 23-paired ESCC tissue samples was performed to discover metabolic dysregulation in ESCC cancerous tissue. A method consisting of support vector machine recursive feature elimination and LIMMA differential expression analysis was utilized to select promising feature genes within transcriptomic data from 179-paired ESCC tissue samples. Joint pathway analysis with genes and metabolites identified relevant metabolic pathways and targets for ESCC.Results: Four metabolites, kynurenine, 1-myristoyl-glycero-3-phosphocholine (LPC(14:0)sn-1), 2-piperidinone, and hippuric acid, were identified as prognostic factors in the preoperative plasma from ESCC patients. A risk score consisting of kynurenine and LPC(14:0)sn-1 significantly improved the prognostic performance of the tumor-node-metastasis staging system and was able to stratify risk for ESCC. Combined tissue metabolomic analysis and support vector machine recursive feature elimination gene selection revealed dysregulated kynurenine pathway as an important metabolic feature of ESCC, including accumulation of tryptophan, formylkynurenine, and kynurenine, as well as up-regulated indoleamine 2,3-dioxygenase 1 in ESCC cancerous tissue.Conclusions: This work identified for the first time four potential prognostic circulating metabolites. In addition, kynurenine pathway metabolism was shown to be up-regulated tryptophan-kynurenine metabolism in ESCC. Results not only provide a metabolite-based risk score system for prognosis, but also improve the understanding of the molecular basis of ESCC onset and progression, and as well as novel potential therapeutic targets for ESCC.
Highlights
Esophageal cancer (EC), a common gastrointestinal malignancy, ranks as the sixth leading cause of cancer death worldwide [1,2,3]
For plasma-based metabolomic profiling study (Group 1), a total of 4,121 metabolic features in electrospray ionization positive mode and 3,046 in electrospray ionization negative mode were extracted from the metabolomic data
Higher plasma levels of kynurenine, 2-piperidinone, and hippuric acid correlated with shorter survival, while higher levels of LPC(14:0)sn-1 correlated with longer survival (Figures 2A–D, Table 2)
Summary
Esophageal cancer (EC), a common gastrointestinal malignancy, ranks as the sixth leading cause of cancer death worldwide [1,2,3]. EC is the fifth most common cancer and the fourth leading cause of death in China [4]. Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of EC in China [5, 6]. Surgical resection with lymphadenectomy is the main treatment for ESCC [7]. Despite advances in surgical management and multidisciplinary treatment of ESCC, prognosis remains poor [8]. There is an urgent need for non-invasive and convenient biomarkers that may assist the clinical decision-making and provide novel insights into tumorigenesis and biology of ESCC [9]. Esophageal squamous cell carcinoma (ESCC) is a gastrointestinal malignancy with a poor prognosis. Studies have shown metabolic reprogramming to be linked to ESCC development, no prognostic metabolic biomarkers or potential therapeutic metabolic targets have been identified
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
