IL1A介导的视黄醇代谢重编程在反流相关胃癌中的预后价值及潜在机制研究

Prognostic Value and Potential Mechanism of IL1A-Mediated Reprogramming of Retinol Metabolism in Reflux-Related Gastric Cancer

摘要: 背景：胃癌是全球常见恶性肿瘤之一。近年来研究表明，胆汁反流可持续刺激胃黏膜并诱导慢性炎症，从而促进肠上皮化生甚至癌变。炎症因子尤其是白细胞介素-1 (IL-1)家族在胃癌发生中发挥重要作用，其中IL1基因区域变异已被证实与胃癌易感性相关。同时，视黄醇代谢通路作为维生素A信号的重要组成部分，在肿瘤细胞分化、干性维持及增殖调控中具有关键作用。方法：基于TCGA数据库筛选具有反流史的胃癌患者并进行差异表达分析，构建预后模型并开展分子分型。进一步结合功能富集、蛋白互作网络及相关性分析，明确关键基因及潜在分子机制，并在AGS细胞中采用IL-1α中和抗体进行体外验证。结果：共筛选出反流相关预后基因并构建风险模型，成功将患者分为不同分子亚型，其中不良预后亚型显著富集于视黄醇代谢通路。IL1A在反流史患者及高危亚型中显著上调，并与视黄醇代谢活性呈正相关。免疫荧光实验显示，阻断IL-1α后ALDH1A3、CRABP2、RDH10及CYP26B1表达明显下降，提示IL1A可能参与视黄醇代谢调控。

Abstract: Background: Gastric cancer is one of the most common malignant tumors worldwide. In recent years, studies have shown that bile reflux can continuously stimulate the gastric mucosa and induce chronic inflammation, thereby promoting intestinal metaplasia and even cancerousness. Inflammatory factors, especially the interleukin-1 (IL-1) family, play an important role in gastric cancer development, and regional variants in the IL1 gene have been confirmed to be associated with gastric cancer susceptibility. At the same time, the retinol metabolism pathway, as an important component of vitamin A signaling, plays a key role in tumor cell differentiation, stem maintenance and proliferation regulation. Methods: Based on the TCGA database, patients with gastric cancer with a history of reflux were screened and differentially analyzed, and a prognostic model was constructed and molecular typing was carried out. Further combined with functional enrichment, protein interaction network and correlation analysis, key genes and potential molecular mechanisms were identified, and IL-1α neutralizing antibody was used in AGS cells for in vitro verification. Results: Reflux-related prognostic genes were screened and a risk model was constructed, and the patients were successfully divided into different molecular subtypes, among which the unfavorable prognostic subtypes were significantly enriched in the retinol metabolism pathway. IL1A was significantly upregulated in patients with a history of reflux and high-risk subtypes, and was positively correlated with retinol metabolic activity. Immunofluorescence assays showed that the expression of ALDH1A3, CRABP2, RDH10 and CYP26B1 decreased significantly after blocking IL-1α, suggesting that IL1A may be involved in the regulation of retinol metabolism.