Abstract

Background According to recent studies, ferroptosis is closely related to the efficacy and prognosis of tumour treatment. However, the role of ferroptosis in esophageal squamous cell carcinoma (ESCC) has not been explored comprehensively. Materials and Methods The esophageal cancer (EC) transcriptome data was downloaded from The Cancer Genome Atlas (TCGA), then analyzed, to obtain the differentially expressed messenger RNA (mRNA), microRNA (miRNA), and long noncoding RNA (lncRNA) between groups with the low and high Ferroptosis Potential Index (FPI) and construct a ferroptosis-associated ceRNA network. In addition, the expression of ARHGEF26-AS1 and miR-372-3p in ESCC cell lines was assessed, and the appropriate cell lines were selected. The interaction between ARHGEF26-AS1, miR-372-3p, and ADAM23 was also determined through a dual-luciferase reporter assay. Moreover, the Western blot, Cell Counting Kit-8 (CCK-8), wound healing, cell viability, and cell death assays were conducted to establish the biological functions of the ARHGEF26-AS1/miR-372-3p/ADAM23 pathway in ESCCs. Results An FPI scoring model reflecting the activity of the ferroptosis pathway was constructed, and a ferroptosis-associated ceRNA network was established. The findings revealed that low expression of ADAM23 and ARHGEF26-AS1 as well as high expression of miR-372-3p was associated with poor prognosis and a lower FPI score in EC patients. Functionally, overexpression of ADAM23 and ARHGEF26-AS1 and the miR-372-3p inhibitor not only promoted ferroptosis in ESCC cells in vitro but also inhibited the proliferation and migration of cells. Mechanistically, ARHGEF26-AS1 upregulated the expression of ADAM23 by competitively binding to miR-372-3p. Conclusions The study showed that the lncRNA, ARHGEF26-AS1 acts as a miR-372-3p sponge that regulates the neuropeptide LGI1 receptor ADAM23 expression. This in turn not only inhibits the proliferation and migration of ESCC cells but also upregulates the ferroptosis pathway. A neuropeptide-related ferroptosis regulatory pathway was identified in this study.

Highlights

  • Esophageal cancer (EC) is a common malignant tumour of the gastrointestinal tract and is associated with a high mortality rate

  • Thereafter, the top 50% patients were grouped into the high Ferroptosis Potential Index (FPI) phenotype score group, and the remaining were classified into the low FPI phenotype score category

  • The results revealed that the Gene Ontology (GO) functions were mainly associated with cholesterol metabolism, fat digestion and absorption, thyroid hormone synthesis, and bile secretion (Figure 2(e))

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Summary

Introduction

Esophageal cancer (EC) is a common malignant tumour of the gastrointestinal tract and is associated with a high mortality rate. The role of ferroptosis in esophageal squamous cell carcinoma (ESCC) has not been explored comprehensively. The findings revealed that low expression of ADAM23 and ARHGEF26-AS1 as well as high expression of miR-372-3p was associated with poor prognosis and a lower FPI score in EC patients. Overexpression of ADAM23 and ARHGEF26-AS1 and the miR-372-3p inhibitor promoted ferroptosis in ESCC cells in vitro and inhibited the proliferation and migration of cells. The study showed that the lncRNA, ARHGEF26-AS1 acts as a miR-372-3p sponge that regulates the neuropeptide LGI1 receptor ADAM23 expression. This in turn inhibits the proliferation and migration of ESCC cells and upregulates the ferroptosis pathway. A neuropeptide-related ferroptosis regulatory pathway was identified in this study

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