Long non-coding RNA LINC00092 inhibits esophageal squamous cell carcinoma progression by promoting ferroptosis through the MAZ/NFE2L2 axis.

BACKGROUND: Esophageal cancer (EC) is the eighth most prevalent malignancy worldwide and exhibits the sixth poorest prognosis. Esophageal squamous cell carcinoma (ESCC) is the predominant pathological subtype. Ferroptosis, an iron-dependent form of cell death, plays a critical role in cancer progression. Long non-coding RNAs (lncRNAs) have emerged as key regulators in the initiation and progression of EC. However, the role of lncRNAs in modulating ferroptosis within EC remains poorly understood. Therefore, this study aimed to identify key ferroptosis-related lncRNAs in ESCC and to investigate the role and mechanism of a specific lncRNA, long intergenic non-protein-coding RNA 92 (LINC00092). METHODS: Bioinformatics analysis was conducted to identify ferroptosis-related lncRNAs, transcription factors (TFs), and genes associated with ESCC. The expression, function, tumor microenvironment, immunotherapy, and downstream molecular pathways were also determined. The expression levels of LINC00092, MYC-associated zinc finger protein (MAZ), and NFE2 like bZIP transcription factor 2 (NFE2L2) were detected using quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemical analysis, and western blotting. Fluorescence in situ hybridization (FISH) was performed to determine the subcellular localization of LINC00092. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, wound healing, Transwell, and flow cytometry apoptosis assays were performed to determine the phenotypes and functions of loss- and gain-of LINC00092. RNA immunoprecipitation (RIP) and luciferase reporter assays were used to evaluate interactions involving LINC00092. The expression of ferroptosis-related proteins was verified by western blotting. RESULTS: LINC00092 was found to be downregulated in ESCC datasets, cell lines, and tissue samples. Bioinformatics analysis revealed that LINC00092 was associated with ferroptosis and negatively correlated with NFE2L2 expression. Further investigations demonstrated that LINC00092 acted as a binder to the TF MAZ, modulating the expression of the ferroptosis-related gene NFE2L2. Overexpression of LINC00092 inhibited ESCC cell progression, whereas its downregulation promoted tumor progression. RIP and luciferase reporter assays confirmed that MAZ was a target of LINC00092, and NFE2L2 was a downstream target of MAZ. Western blot analysis showed that LINC00092 enhanced ferroptosis in ESCC cells. The LINC00092/MAZ/NFE2L2 axis appeared to inhibit cancer progression by promoting ferroptosis through the regulation of NFE2L2 and sequestration of the TF MAZ. CONCLUSIONS: LINC00092 exerts tumor-suppressive effects in ESCC cells by inhibiting cancer progression through the LINC00092/MAZ/NFE2L2 axis and promoting ferroptosis. Therefore, LINC00092 may serve as a potential therapeutic target for ESCC.