• AGTRAP can influence various cellular behaviors in HCC, including proliferation, migration, invasion, and apoptosis. • AGTRAP promotes the formation of the tumor-supportive M2 phenotype while inhibiting the tumor-suppressive M1 phenotype. • The AGTRAP-p38 MAPK regulatory pathway is crucial in altering macrophage phenotypes, resulting in an immunosuppressive tumor microenvironment. • AGTRAP facilitates exosome-mediated signaling between cancer cells and macrophages through the p38 MAPK pathway, ultimately driving the malignant progression of HCC. Angiotensin II Receptor-Associated Protein (AGTRAP) is markedly overexpressed in hepatocellular carcinoma (HCC) cases associated with poor prognosis; however, its precise functional role remains inadequately elucidated. This study aimed to elucidate the functional role of AGTRAP in HCC progression and its impact on the tumor microenvironment (TME). We knocked down AGTRAP expression in HCC cell lines (HepG2 and SK-hep1) using shRNA and evaluated the impact of AGTRAP knockdown on hepatocellular carcinoma cells through proliferation, invasion, and migration. Immunofluorescence staining was used to analyze the distribution of M1-type and M2-type macrophages in HCC patient tissues. The signaling pathway mechanism by which AGTRAP regulates macrophage polarization was further analyzed, focusing on the p38 MAPK pathway. The effects and mechanisms of exosomes derived from AGTRAP-knockdown HCC cells on macrophage polarization were investigated. Silencing AGTRAP significantly enhanced apoptosis, disrupted cell cycle progression, and diminished the invasive and migratory capacities of HCC cells.Tumors with high AGTRAP expression exhibited increased M2-type macrophages and decreased M1-type macrophages, indicating a shift in the TME towards an immunosuppressive state.Mechanistic studies revealed that AGTRAP modulates macrophage polarization by interacting with the p38 MAPK signaling pathway.Exosomes derived from AGTRAP-silenced HCC cells also influenced macrophage polarization via the p38 MAPK pathway. AGTRAP facilitates HCC progression by mediating exosomal communication between cancer cells and macrophages via the p38 MAPK pathway, underscoring its pivotal role in shaping the immunosuppressive tumor microenvironment.
Liu et al. (Wed,) studied this question.