Fig. 4

Multi-omics analysis identifies CD39 expression as a target in the circTMEM181-miR-488-3p axis in macrophages. a Volcano plot shows varied protein profiles between heavy (H) and light (L) medium. Significantly upregulated proteins in the heavy group are colored in red, while significantly down-regulated proteins in light group are in blue. THP-1 co-cultured with exosomes from HepG2^OE (THP-1^co−exoOE) and paired THP-1 co-cultured with exosomes from HepG2^Ctrl (THP-1^co−exoCtrl) were subjected to SILAC. THP-1^co−exoOE were co-cultured with heavy medium (H^OE), and THP-1^co−exoCtrl with light medium (L^Ctrl) (Left). THP-1^co−exoCtrl were co-cultured with heavy medium (H^Ctrl), and THP-1^co−exoOE with light medium (L^OE) (Right). b Venn diagrams show that 165 proteins were upregulated in the intersection of these two forward–reverse experiments (Left). Pathway enrichment of the differentiated proteins according to KEGG and GO analysis (Right). c Venn diagrams show 12 mRNAs in the overlap of mRNAs that miRNA 488-3p can target and upregulated proteins in THP-1^circOE. d ENTPD1 and PLAC8 connect to miR-488-3p by TargetScan prediction. e, f The level of ENTPD1 was detected in different conditions manipulating circTMEM181, GW4869, or miR-488-3p (t test, ***: p < 0.001, **: p < 0.01, *: p < 0.05). g Summary of three scRNAseq samples of human HCC tumor tissues from GEO datasets (GSE140228 (10 ×), GSE140228 (Smartseq2) ,and GSE125449). Monocytes/macrophages in the HCC tumor microenvironment show high expression of CD39 across the three datasets. h UMAP analysis showing scRNAseq data of different tumor-infiltrating immune cells in HCC (GSE140228 (10 ×)). Tumor-infiltrating macrophages express a high level of CD39 (ENTPD1) but do not express CD73 (NT5E)