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

Abstract

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 was mediated by IDO1 metabolite kynurenine and integrin β1. A popliteal lymph nodemetastasis model was established for verifying metastatic promotion of IDO1 and COL12A1 in GC. Conclusions IDO1 and COL12A1 synergistically promoted GC metastasis. The novel findings suggested that both IDO1 and COL12A1 may be promising targets on anti-cancer treatment in GC. Electronic supplementary material The online version of this article (10.1186/s13046-019-1318-5) contains supplementary material, which is available to authorized users.

Review: Gastric cancer: Basic aspects

“…Moreover, in this study, immune cell subtypes did not cluster clearly according to the samples' MSI/MSS status 24 . In a different study, Xiang et al 25 identified IDO1 to be highly expressed in 4 GC cell lines (AGS, Hs746T, SGC‐7901 and MKN‐45) and to be positively associated with extracellular matrix formation and collagen processing. Expression of collagens in tumour tissues could not only ignite tumour invasion and metastasis but also prevent T cells from entering into the tumour tissue and impair a proper antitumour immune response.…”

Integrated Transcriptome Analyses and Experimental Verifications of Mesenchymal-Associated TNFRSF1A as a Diagnostic and Prognostic Biomarker in Gliomas

“…WGCNA has already been successfully utilized in many studies (9,10). Using the genome-transcriptiomic data of gastric cancer (GC) cell lines from Cancer Cell Line Encyclopedia (CCLE), Xiang et al found that upregulated COL12A1 and LOXL2 were associated with IDO1 expression, and further biological experiments verified that IDO1 and COL12A1 could synergistically improve GC metastasis (11). Zhang et al adopted WGCNA and proteinprotein interaction (PPI) analysis to reveal that Tgfβ2, Wnt9a, and Fgfr4 were the hub genes regulating the differentiation of aging satellite cells (12).…”

The Diagnostic Value of LGALS1 in Esophageal Cancer and its Potential Molecular Pathways via Bioinformatic Analysis

“…Increased IDO1 expression promotes gastric cancer cell migration. Interfering with IDO1 expression in GC cells reduced LOXL2, COL6A1, COL6A2, and COL12A1 mRNA and protein expressions [37]. These results indicate that these hub genes are related to tumorigenesis and development.…”