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AFP shields hepatocellular carcinoma from macrophage phagocytosis by regulating HuR-mediated CD47 translocation in
Yinglian Pan1, Qiushi Yin2, Zhaoliang Wang3
1Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical University, Haikou, Hainan Province, PR China; Department of Medical Oncology, the First Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province, PR China.
Objectives:
Alpha fetoprotein(AFP) overexpression connecting with macrophage dysfunction remain poorly defined. In this study, explore AFP regulates macrophage immunomodulation in hepatocellular carcinoma(HCC) through comprehensive in vitro and in vivo studies.
Methods:
Immunohistochemical and immunofluorescence staining was used to analyze the relativity of AFP and cellular membrane CD47 expression in clinical 30 HCC tissues, and the expression of AFP and CD47 in HCC cells. The intelligent living-cell high-throughput imaging analyzer was applied to dynamically track and image of macrophages to phagocytize HCC cells. The effect of AFP on regulating the level of CD47 in cellular membrane and growth of tumor in vivo was performed by animal experiment. The association of AFP and CD47 in HCC cells was detected by single cell analysis.
Results:
The present results indicated that AFP upregulated the localization of CD47 on the HCC cell surface. CD47 overexpression stimulates HCC to escape immune surveillance by transmitting "don't eat me" signals to macrophages, lead to inhibit macrophage to phagocytize HCC cells. Mechanistically, the results demonstrated that AFP enhanced CD47 membrane translocation by interacting with Hu-Antigen R(HuR), an RNA-binding protein that regulates mRNA stability and translation. AFP alters the subcellular distribution of HuR, increasing its cytoplasmic accumulation and binding to CD47 transcript.
Conclusions:
AFP enhanced CD47 membrane translocation by interacting with HuR. These findings proved that AFP could inhibit macrophage to phagocytize HCC cells by upregulating the localization of CD47 on the HCC cell surface. Combination of AFP with CD47 blockade may be a potential therapeutic strategy for HCC treatment.
Insights
Alpha fetoprotein (AFP) overexpression in hepatocellular carcinoma (HCC) promotes tumor immune evasion by upregulating CD47 on cancer cells. This blocks macrophages from engulfing tumor cells, suggesting AFP and CD47 as therapeutic targets.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Alpha fetoprotein (AFP) overexpression is linked to macrophage dysfunction in hepatocellular carcinoma (HCC).
- The precise mechanisms by which AFP influences macrophage immunomodulation in HCC remain unclear.
- Understanding this interaction is crucial for developing effective HCC therapies.
Purpose of the Study:
- To investigate how AFP regulates macrophage immunomodulation in HCC.
- To explore the role of AFP in macrophage dysfunction within the HCC tumor microenvironment.
- To elucidate the molecular pathways connecting AFP, CD47, and macrophage phagocytosis in HCC.
Main Methods:
- Analyzed AFP and CD47 expression in HCC tissues and cells using immunohistochemistry and immunofluorescence.
- Utilized live-cell imaging to track macrophage phagocytosis of HCC cells.
- Conducted in vivo animal experiments to assess AFP's effect on CD47 and tumor growth.
- Employed single-cell analysis to determine the association between AFP and CD47 in HCC cells.
Main Results:
- AFP was found to upregulate CD47 expression on the surface of HCC cells.
- Upregulated CD47 on HCC cells transmitted "don't eat me" signals, inhibiting macrophage phagocytosis and promoting immune escape.
- Mechanistically, AFP enhances CD47 membrane translocation by interacting with Hu-Antigen R (HuR), increasing its cytoplasmic accumulation and binding to CD47 mRNA.
Conclusions:
- AFP promotes HCC immune evasion by increasing CD47 surface expression, thereby inhibiting macrophage phagocytosis.
- AFP interacts with HuR to regulate CD47 translocation, offering a molecular explanation for AFP-mediated immune suppression.
- Targeting both AFP and CD47 blockade presents a promising therapeutic strategy for HCC treatment.
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