A positive feedback between IDO1 metabolite and COL12A1 via MAPK pathway to promote gastric cancer metastasis

作者：Zhen Xiang, Jun Li, Shuzheng Song, Jiexuan Wang, Wei Cai, Wenjun Hu, Jun Ji, Zhenggang Zhu, Lu Zang, Ranlin Yan, Yingyan Yu · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2019 · DOI：10.1186/s13046-019-1318-5 · 被引用次数：146 · 研究领域：Tryptophan and brain disorders、Ferroptosis and cancer prognosis、Immune cells in cancer

BACKGROUND: IDO1 (Indoleamine 2,3-dioxygenase 1) inhibits host anti-tumor immune response by exhausting tryptophan in tumor microenvironment, but the pathogenic mechanisms of IDO1 in gastric cancer (GC) cells need to be further explored. METHODS: The aim of this study was to use CCLE (Cancer Cell Line Encyclopedia) transcriptomic data of GC cell lines for WGCNA (Weighted Gene Co-expression Network Analysis) analysis, and explore the potential functions and mechanisms of IDO1 in GC progression in vitro and in vivo. RESULTS: The higher expression level of IDO1 was identified in 4 out of 7 GC cell lines. Increased IDO1 expression strongly promoted cell migration via its metabolite kynurenine and was associated with pathways of immune activation according to GSEA (Gene Set Enrichment Analysis). The functions of IDO1 were closely associated with extracellular matrix, collagen metabolic and catabolic process by WGCNA analysis. Among five hub genes (AXL, SGCE, COL12A1, ANTXR1, LOXL2), COL12A1 and LOXL2 were upregulated in GC tissues. IDO1 disclosed positive correlation with six collagen genes by coefficient matrix diagram. Knockdown of IDO1 decreased the expression of LOXL2, COL6A1, COL6A2 and COL12A1 in GC cells in both mRNA and protein levels. Of them, knockdown of COL12A1 inhibited cell migration more apparently than knockdown of others. IDO1 and COL12A1 revealed synergistic efficacy on promoting cell migration via a positive feedback sustained by MAPK pathway. This bioprocess wa...