Exosomal miR-628-5p from M1 polarized macrophages hinders m6A modification of circFUT8 to suppress hepatocellular carcinoma progression

Abstract

Background: Hepatocellular carcinoma (HCC) is the most common type of liver cancer. CircFUT8 has been shown to be upregulated in cancers, but its function in HCC remains unclear. Tumor-associated macrophages (TAMs) are one of the main components of the tumor microenvironment (TME), and M1 macrophages function as tumor suppressors in cancers. Exosomes exert an important role in the TME, and circRNAs can be modified by m6A. We investigated the function of circFUT8 in HCC and its interaction with exosomes, M1 macrophages, and m6A. Methods: CircFUT8 expression was detected in HCC cells, and its effects on HCC cell growth were verified through functional assays. Mechanism assays including RNA pull down, RNA-binding protein immunoprecipitation (RIP), and luciferase reporter assays were undertaken to verify how circFUT8 may interact with miR-628-5p, and how these molecules may modulate HCC cell malignancy via interacting with exosomes and macrophages. Results: CircFUT8 was upregulated in HCC cells and it accelerated HCC cell growth. Exosomes derived from M1 macrophages transferred miR-628-5p to HCC cells to inhibit human methyltransferase-like 14 (METTL14) expression. METTL14 promoted circFUT8 m6A modification and facilitated its nuclear export to the cytoplasm, where M1 macrophages regulated the circFUT8/miR-552-3p/CHMP4B pathway, thereby suppressing HCC progression. Conclusion: M1 macrophages-derived exosomal miR-628-5p inhibited the m6A modification of circFUT8, inhibiting HCC development. Graphical Abstract: [Figure not available: see fulltext.]