Identification of Downregulated Exosome-Associated Gene ENPP1 as a Novel Lipid Metabolism and Immune-Associated Biomarker for Hepatocellular Carcinoma

Abstract

Exosome plays an important role in the occurrence and development of tumors, such as hepatocellular carcinoma (LIHC). However, the functions and mechanisms of exosome-associated molecules in LIHC are still underexplored. Here, we investigated the role of the exosome-related gene ENPP1 in LIHC. Comprehensive bioinformatics from multiple databases revealed that ENPP1 was significantly downregulated in LIHC tissues. The patients with downregulated ENPP1 displayed a poor prognosis. Immunohistochemistry (IHC) was used to further confirm the downregulated ENPP1 in LIHC tissues. In addition, the coexpression network of ENPP1 was also explored to understand its roles in the underlying signaling pathways, including fatty acid degradation and the PPAR signaling pathway. Simultaneously, GSEA analysis indicated the potential roles of ENPP1 in the lipid metabolism-associated signaling pathways in the pathogenesis of LIHC, including fatty acid metabolism, fatty acid synthesis, and so on. Finally, immunological analysis indicated that ENPP1 might also be involved in multiple immune-related features, including immunoinhibitors, immunostimulators, and chemokines. Taken together, these findings could enhance our understanding of ENPP1 in LIHC pathogenesis and immune response and provide a new target for ENPP1-related immunotherapy in clinical treatment.

Small extracellular vesicle-mediated metabolic reprogramming: from tumors to pre-metastatic niche formation

“…sEV CD147 could suppress FAO by suppressing p38 MAPK signaling to down-regulate the expressions of PPARα and its target genes of CPT1A and ACOX1, which consequently reprogrammed cancer cell lipid metabolism except for its functions in de novo lipogenesis [ 36 ]. Ectonu nucleotide pyrophosphatase/phosphodiesterase 1(ENPP1) is a type II transmembrane glycoprotein, a decrease in which is connected with poor prognosis in HCC patients [ 44 , 45 ]. Down-regulated sEV-associated ENPP1 and FA fatty acid degradation and PPAR signaling pathways are the signaling pathways for the enrichment of sEV ENPP1 co-expression molecules [ 46 ].…”

“…Down-regulated sEV-associated ENPP1 and FA fatty acid degradation and PPAR signaling pathways are the signaling pathways for the enrichment of sEV ENPP1 co-expression molecules [ 46 ]. Additionally, ENPP1 may take part in the supervision of other lipid metabolic routes, including FA ω-oxidation [ 45 ]. The above studies confirmed that sEVs reprogram cancer metabolism in the anabolism and catabolism of lipids through their cargos, thus promoting the occurrence and development of tumors.…”