The hepatitis B virus X protein (HBx) is a central oncogenic driver in hepatocellular carcinoma (HCC). Although glypican-3 (GPC3) is a phosphatidylinositol proteoglycan-specific biomarker for HCC. However, the combined role of HBx and GPC3 in mediating HCC cell evasion from macrophage phagocytosis remains unclear. Here, we demonstrate that HBx modulates macrophage phagocytosis by regulating GPC3 membrane morphology. Analysis of tissues from 30 patients with hepatocellular carcinoma revealed concomitant upregulation of HBx and GPC3 in tumour specimens. Mechanistically, HBx alters ERK site phosphorylation, thereby influencing the enzymatic activity of Furin protease-which cleaves GPC3-and consequently orchestrating morphological changes of membrane-associated GPC3. To functionally validate this, THP-1 cells were polarized to M1 macrophages and co-cultured with HCC cells. Notably, HBx directly impaired macrophage phagocytosis of HCC cells, an effect mediated through GPC3 morphological dynamics. Collectively, these findings indicate that HBx suppresses macrophage phagocytosis of HCC cells by remodelling membrane-associated GPC3.
Wu et al. (Wed,) studied this question.