Aberrations in ion channels interacting with lipid metabolism and epithelial-mesenchymal transition in esophageal squamous cell carcinoma.

Abstract

Esophageal squamous cell carcinoma (ESCC) is the most prevalent malignant gastrointestinal tumor. Ion channels contribute to tumor growth and progression through interactions with their neighboring molecules including lipids. The dysregulation of membrane ion channels and lipid metabolism may contribute to the epithelial-mesenchymal transition (EMT), leading to metastatic progression. Herein, transcriptome profiles of patients with ESCC were analyzed by performing differential gene expression and weighted gene co-expression network analysis to identify the altered ion channels, lipid metabolism- and EMT-related genes in ESCC. A total of 1,081 differentially expressed genes, including 113 ion channels, 487 lipid metabolism-related, and 537 EMT-related genes, were identified in patients with ESCC. Thereafter, EMT scores were correlated with altered co-expressed genes. The altered co-expressed genes indicated a correlation with EMT signatures. Interactions among 22 ion channels with 3 hub lipid metabolism- and 13 hub EMT-related proteins were determined using protein-protein interaction networks. A pathway map was generated to depict deregulated signaling pathways including insulin resistance and the estrogen receptor-Ca2+ signaling pathway in ESCC. The relationship between potential ion channels and 5-year survival rates in ESCC was determined using Kaplan-Meier plots and Cox proportional hazard regression analysis. Inositol 1,4,5-trisphosphate receptor type 3 (ITPR3) was found to be associated with poor prognosis of patients with ESCC. Additionally, drugs interacting with potential ion channels, including GJA1 and ITPR3, were identified. Understanding alterations in ion channels with lipid metabolism and EMT in ESCC pathophysiology would most likely provide potential targets for the better treatment of patients with ESCC.