Deciphering the role of tryptophan metabolism-associated genes ECHS1 and ALDH2 in gastric cancer: implications for tumor immunity and personalized therapy

作者：Lexin Wang, Xue Zhou, Haisheng Yan, Yaping Miao, Binbin Wang, Yuheng Gu, Weining Fan, Ke Xu, Shangke Huang, Jie Liu · 发表于：Frontiers in Immunology · 年份：2024 · DOI：10.3389/fimmu.2024.1460308 · 被引用次数：18 · 研究领域：Tryptophan and brain disorders、Ferroptosis and cancer prognosis、Cancer, Hypoxia, and Metabolism

Background Tryptophan Metabolism-associated Genes (TMGs), such as ECHS1 and ALDH2, are crucial in cancer progression through immunosuppressive mechanisms, particularly in Gastric Cancer (GC). This study explores their effects on the Tumor Microenvironment (TME). Additionally, it examines their potential as novel immunotherapy targets. Methods We utilized single-cell and bulk transcriptomic technologies to analyze the heterogeneity of GC. Non-negative Matrix Factorization (NMF) clustering identified key TMGs, and extensive RNA-seq analyses were performed to pinpoint prognostic genes and potential immunotherapy targets. Furthermore, through PCR analyses we found that ECHS1 and ALDH2 gene expression plays a regulatory role in the migration, invasion and inflammatory factor in AGS and SNU-1 cell lines. The interference effect of si-ECHS1 and ad-ALDH2 was validated using cell scratch assay in AGS and SNU-1 cell line. Results We observed a statistically significant correlation between ECHS1 and ALDH2 expression and increased TME heterogeneity. Our findings also revealed that ECHS1 down-regulation and ALDH2 up-regulation contribute to reduced TME heterogeneity, decreased inflammation, and inhibited AGS and SNU-1 tumor cells migration and proliferation. GSVA enrichment analysis highlighted the NF-kappa B(NF-κB) signaling pathway as specifically regulated by TMGs. Furthermore,ECHS1 and ALDH2 modulated CD8+ and CD4+ T cell activities, impacting GC progression. In vitro experiments furt...