Metabolomic Characterization Reveals ILF2 and ILF3 Affected Metabolic Adaptions in Esophageal Squamous Cell Carcinoma

Abstract

Esophageal cancer (EC) is a common malignant disease in eastern countries. However, a study of the metabolomic characteristics associated with other biological factors in esophageal squamous cell carcinoma (ESCC) is limited. Interleukin enhancer binding factor 2 (ILF2) and ILF3, double-stranded RNA-binding proteins, have been reported to contribute to the occurrence and development of various types of malignancy. Nevertheless, the underlying functions of ILF2 and ILF3 in ESCC metabolic reprogramming have never been reported. This study aimed to contribute to the metabolic characterization of ESCC and to investigate the metabolomic alterations associated with ILF2 and ILF3 in ESCC tissues. Here, we identified 112 differential metabolites, which were mainly enriched in phosphatidylcholine biosynthesis, fatty acid metabolism, and amino acid metabolism pathways, based on liquid chromatography–mass spectrometry and capillary electrophoresis–mass spectrometry approaches using ESCC tissues and paired para-cancer tissues from twenty-eight ESCC patients. In addition, ILF2 and ILF3 expression were significantly elevated in EC tissues compared to the histologically normal samples, and closely associated with PI3K/AKT and MAPK signaling pathways in ESCC. Moreover, in ESCC tissues with a high ILF2 expression, several short-chain acyl-carnitines (C3:0, C4:0, and C5:0) related to the BCAA metabolic pathway and long-chain acyl-carnitines (C14:0, C16:0, C16:0-OH, and C18:0) involved in the oxidation of fatty acids were obviously upregulated. Additionally, a series of intermediate metabolites involved in the glycolysis pathway, including G6P/F6P, F1,6BP, DHAP, G3P, and 2,3BPG, were remarkably downregulated in highly ILF3-expressed ESCC tissues compared with the corresponding para-cancer tissues. Overall, these findings may provide evidence for the roles of ILF2 and ILF3 during the process of ESCC metabolic alterations, and new insights into the development of early diagnosis and treatment for ESCC. Further investigation is needed to clarify the underlying mechanism of ILF2 and ILF3 on acyl-carnitines and the glycolysis pathway, respectively.

Serum Metabolite Biomarkers for Pancreatic Tumors: Neuroendocrine and Pancreatic Ductal Adenocarcinomas—A Preliminary Study

“…Metabolites that we found to differentiate pancreatic tumors were additionally noted in PubMed database to be linked with other gastrointestinal malignancies: esophageal [ 56 , 57 , 58 , 59 , 60 , 61 , 62 ], stomach/gastric (GC) [ 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ], liver/ hepatocellular carcinoma (HCC) [ 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 ], and colon/colorectal (CRC) [ 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 ] ( Supplement Table S2 ). We noticed that there is still limited knowledge concerning metabolism disturbances linked to creatine and phosphatidylcholine, especially C2 and PC 34.…”

High expression of HNRNPR in ESCA combined with 18F-FDG PET/CT metabolic parameters are novel biomarkers for preoperative diagnosis of ESCA

“…In this experiment, through the STRING, there is PPI between HNRNPR and PTBP1, RBMX and ILF2 in addition to proteins from the same family. Among these, ILF2 [ 41 ] has been shown to affect the metabolic adaptation of ESCC. PPI is also one of the factors promoting the formation of stress granules mentioned previously.…”

Identification and Validation of a Prognostic Immune-Related Gene Signature in Esophageal Squamous Cell Carcinoma

“…ILF3 has been reported to contribute to the development of various cancers ( Hu et al, 2013 ; Cheng et al, 2018 ; Liu et al, 2019 ). High expression of ILF3 was shown to be involved in the metabolic alterations in ESCC patients, especially for the intermediate metabolites of the glycolysis pathway ( Zang et al, 2021 ). Through survival analysis, we found that the expression of PSMD6 , RABEP2 , GRN , and STC2 were related to a poor ESCC prognosis, while the expression of ITCH , ILF3 , and PSMC4 were related to a good prognosis.…”