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Background: Previous studies have shown that necroptosis-related long noncoding RNA (lncRNA) risk models can be used to predict prognosis and immune infiltration in patients with esophageal cancer. However, further analysis of the regulatory mechanisms of necroptosis-related lncRNAs used in risk models remains to be conducted. The purpose of the present study was to identify valuable necroptosis-related lncRNAs in esophageal cancer and to verify their molecular and cellular functions. Methods: Esophageal cancer data were downloaded from The Cancer Genome Atlas (TCGA). The expression of eight genes (LINC00299, AC090912.2, AC244197.2, AL158166.1, AC079684.1, AP003696.1, AC079684.1 and AP003696.1) in the necroptosis-related lncRNA risk model, their relationships with clinicopathological stage, and their diagnostic receiver operating characteristic (ROC) curves were analyzed. The prognostic value of these lncRNAs for overall survival (OS) and disease specific survival (DSS) was analyzed, and time-dependent ROC curves were generated. The AP003696.1 target gene (lncRNA ENSG00000253385.1) was further investigated through immune infiltration analysis, Gene Ontology/Kyoto Encyclopedia of Genes and Genomes (GO/KEGG) enrichment analyses, and gene coexpression analysis. Finally, in vitro functional assays based on lncRNA ENSG00000253385.1 were conducted to explore its regulatory role in esophageal cancer. Results: A bioinformatics approach was used to study the eight genes in the necroptosis-related lncRNA risk model. AP003696.1 (lncRNA ENSG00000253385.1) was highly expressed in esophageal cancer tissues, and its high expression was correlated with poor OS and DFdS. Both univariate and multivariate Cox regression analyses revealed that lncRNA ENSG00000253385.1 is an independent prognostic factor. The lncRNA ENSG00000253385.1 gene was demonstrated to play a definite role in the invasion of esophageal cancer immune cells and in signaling pathways in these cells. In vitro cell functional assays revealed that lncRNA ENSG00000253385.1 expression was elevated in the KYSE150 and KYSE410 esophageal cancer cell lines. Small interfering RNA (siRNA)-mediated silencing of lncRNA ENSG00000253385.1 significantly inhibited the proliferation, migration, and invasion of KYSE150 and KYSE410 cells, as well as promoted their apoptosis. Conclusions: The ENSG00000253385.1 gene may be a key gene in the occurrence, development, and prognosis of esophageal cancer. These findings provide new ideas and references for the screening of therapeutic targets, as well as the development of targeted drugs, for esophageal cancer treatment.

Abstract Background Esophageal cancer (EC) is a deadly disease with limited therapeutic options. Although circulating tumor DNA (ctDNA) could be a promising tool in this regard, the availiable evidence is limited. We performed a systematic review and meta-analysis to summarize the clinical applicability of the next-generation sequencing (NGS) and droplet digital polymerase chain reaction (ddPCR) technology on the ctDNA detection of the EC and listed the current challenges. Methods We systematically searched MEDLINE (via PubMed), Embase (via OVID), ISI Web of Science database and Cochrane Library from January, 2000 to April, 2023. Progression-free survival (PFS) and overall survival (OS) were set as primary outcome endpoints. Pathologic response was evaluated by tumor regression grade (TRG), according to the eighth edition of the American Joint Committee on Cancer (AJCC). Major pathologic regression (MPR) was defined as TRG 1 and 2. The MPR was set as secondary endpoint. Hazard rate (HR) and associated 95% CI were used as the effect indicators the association between ctDNA and prognosis of EC. MPR rates were also calculated. Fixed-effect model (Inverse Variance) or random-effect model (Mantel-Haenszel method) was performed depending on the statistically heterogeneity. Results Twenty-two studies, containing 1144 patients with EC, were included in this meta-analysis. The results showed that OS (HR = 3.87; 95% CI, 2.86–5.23) and PFS (HR = 4.28; 95% CI, 3.34–5.48) were shorter in ctDNA-positive patients. In the neoadjuvant therapy, the sensitivity analysis showed the clarified HR of ctDNA-positive was 1.13(95% CI, 1.01–1.28). We also found that TP53, NOTCH1, CCND1 and CNKN2A are the most frequent mutation genes. Conclusions Positive ctDNA is associated with poor prognosis, which demonstrated clinical value of ctDNA. Longitudinal ctDNA monitoring showed potential prognostic value in the neoadjuvant therapy. In an era of precision medicine, ctDNA could be a promising tool to individualize treatment planning and to improve outcomes in EC. PROSPERO registration number CRD42023412465.