m6A-modified MIR670HG suppresses tumor liver metastasis through enhancing Kupffer cell phagocytosis.

Abstract

Liver metastases are frequently observed in various malignancies, including hepatocellular carcinoma, colorectal cancer, pancreatic cancer, and melanoma. As hepatic resident macrophages, Kupffer cells play a crucial role in resisting liver metastasis by phagocytosing and clearing invading tumor cells. However, the molecular mechanisms regulating Kupffer cell phagocytosis and liver metastasis remain largely unknown. Here, we demonstrate that the MIR670 host gene (MIR670HG) significantly suppresses tumor liver metastasis by enhancing phagocytosis of various tumor cells by Kupffer cells. CD24 was identified as a downstream target and critical mediator of MIR670HG in promoting Kupffer cell phagocytosis and inhibiting tumor liver metastasis. Further investigations revealed that MIR670HG interacts with the m⁶A reader FXR1 and DNA 5-methylcytosine dioxygenase TET1 in an m⁶A modification-dependent manner. These interactions reduce the binding of TET1 to CD24 promoter, leading to increased DNA methylation at CD24 promoter and transcriptional suppression of CD24. Mutation of the m⁶A modification site abolishes the ability of MIR670HG to suppress CD24, promote Kupffer cell phagocytosis, and inhibit liver metastasis. In clinical tissue samples, MIR670HG expression negatively correlated with CD24 and liver metastasis. These findings suggest that m⁶A-modified MIR670HG promotes phagocytosis of tumor cells by Kupffer cells and suppresses liver metastasis by epigenetically downregulating CD24.