Mechanism of HBV-positive liver cancer cell exosomal miR-142-3p by inducing ferroptosis of M1 macrophages to promote liver cancer progression

BACKGROUND: Exosomes are becoming an important mediator of the interaction between tumor cells and the microenvironment. Ferroptosis is a newly discovered type of cell death. However, its role in the progression of liver cancer is largely unknown. The aim of the presents study was to analyze the mechanism by which hepatitis B virus (HBV)-positive liver cancer secretes exosomes to mediate the iron death of M1 macrophages, thereby promoting the development of liver cancer. METHODS: Liver cancer tissues and peripheral blood with positive and negative clinical HBV infection were collected, and M-type macrophages, miR-142-3p, and recombinant solute carrier family 3, member 2 (SLC3A2) expressions were detected in the samples. CD80(+) M1 macrophages and CD163(+) M2 macrophages were isolated from the 2 tissues, and levels of miR-142-3p, SLC3A2, and ferroptosis markers were detected. Exosomes of HBV-positive hepatocellular carcinoma (HCC) cells were isolated and co-cultured with M1 macrophages to observe their effect on the invasion ability of HCC cells. RESULTS: The expression of miR-142-3p significantly increased in the exosomes extracted from the peripheral blood of patients with HBV-positive liver cancer. Genes related to intracellular iron metabolism and homeostasis, such as ferritin heavy chain 1 (FTH1), transferrin receptor 1 (TfR1), recombinant glutathione peroxidase 4 (GPX4), and activating transcription factor 4 (ATF4), had abnormal expression levels in M1 macrophages. HBV-positive HCC exosomes treated with M1-type macrophages had a weakened inhibitory effect on the invasion of HCC cells, but ferroptosis inhibitors could reverse the effect of HBV-positive HCC exosomes treated M1-type macrophages on HCC cells. Knockdown of the expression of miR-142-3p can also weaken the invasive ability of liver cancer cells. CONCLUSIONS: The results of the present study confirmed that HBV-positive liver cancer cell exosomal miR-142-3p can promote the progression of liver cancer by inducing iron death of M1-type macrophages.