Tumor-derived exosomes carry LCN2 to block Nedd4-1-mediated SR-BI ubiquitination, inducing M2 macrophage polarization and promoting hepatocellular carcinoma growth

Hepatocellular carcinoma (HCC) is a highly prevalent and lethal malignancy with complex pathogenesis and limited treatment options. Exosomes play crucial roles in HCC development and progression. This study aimed to comprehensively investigate the differential expression and functional roles of lipocalin-2 (LCN2) in HCC exosomes. Bioinformatics analysis of the GSE199509 dataset identified 4518 differential expression genes (DEGs) between HCC patient-derived exosomes and normal controls, with LCN2 being highly expressed in HCC exosomes. In vitro experiments showed that LCN2 was significantly enriched in exosomes from HCC cell lines (SMMC-7721 and HepG2). HCC-derived exosomes induced M2 macrophage polarization, which promoted HCC cell migration, invasion, and proliferation. Knockdown of LCN2 attenuated HCC exosome-induced M2 macrophage polarization and reduced the pro-tumor effects on HCC cells. Mechanistically, LCN2 inhibited Nedd4-1-mediated ubiquitination and degradation of SR-BI in a Nedd4-1-dependent manner. SR-BI overexpression reversed the effects of LCN2 knockdown on macrophage polarization and HCC cell proliferation. In vivo mouse models demonstrated that LCN2 knockdown inhibited tumor growth in wild-type mice but not in SR-BI knockout mice. These findings suggest that LCN2 plays a pivotal role in HCC progression through modulating macrophage polarization and interacting with SR-BI. Targeting the LCN2-SR-BI axis may represent a novel therapeutic strategy for HCC. Additionally, exosomal LCN2 could be a potential biomarker for HCC diagnosis and prognosis. However, further pre-clinical and clinical studies are needed to validate these findings.