What question did this study set out to answer?

The aim is to investigate the role and mechanisms of CD47 in hepatocellular carcinoma, focusing on its potential as a therapeutic target.

April 13, 2026Open Access

CD47 exacerbates hepatocellular carcinoma progression by promoting polarisation of tumour-associated macrophages towards the M2 phenotype via the SHP2/SYK/ROS/SIRT1 axis

Key Points

The aim is to investigate the role and mechanisms of CD47 in hepatocellular carcinoma, focusing on its potential as a therapeutic target.
Utilized lentiviral methods for CD47 expression changes in Huh-7 cells.
Co-cultured hepatocellular carcinoma cells with THP-1 cells and treated with specific compounds.
Conducted Western blotting and immunofluorescence to assess signaling pathways.
Measured arginase-1 and TNFα via ELISA in co-culture supernatants.
Performed angiogenesis assays and cell proliferation analysis using CCK-8.
CD47 promotes M2 polarization of tumor-associated macrophages, enhancing tumor growth.
In vivo experiments showed that CD47 knockdown inhibited tumor progression significantly.
Alterations in protein expressions (e.g., p-SHP2, p-SIRT1) were observed in macrophages.
SHP2 overexpression enhanced tumor suppression, while SHP2 knockdown facilitated tumor growth.

Abstract

Liver cancer is the second most common cause of cancer-related deaths worldwide. The primary form of liver cancer is hepatocellular carcinoma (HCC). This study aims to explore the function of the CD47 molecule in HCC to deepen the understanding of its role and mechanisms, laying the foundation for CD47 as a target for the diagnosis and treatment of liver cancer. Analysing specific proteins in HCC using bioinformatics. Lentiviral methods were used to establish differentially expressed CD47 hepatocellular carcinoma cell lines Huh-7, including CD47 overexpression, interference, and control cells. Hepatocellular carcinoma and THP-1 cells were co-cultured and then treated with PHPS1 and SRT1720. Western blotting was used to detect protein changes in relevant signaling pathways in THP-1 cells. Immunofluorescence analysis was used to assess p-SHP2 and p-SYK expression. ELISA was employed to measure changes in arginase-1 and TNFα concentrations in the supernatant of co-cultured cells. Angiogenesis assays were conducted to assess the angiogenic capacity of each group. The CCK-8 (cell count kit-8) method was used to determine the proliferation of Huh-7 cells. To further validate these observations, we conducted xenotransplantation experiments in mice. Bioinformatics analyses revealed CD47-specific expression in HCC. CD47 in Huh-7 cells can promote the relative protein expression of p-SHP2, p-SIRT1, KLF4, HIF1α, VEGFA, and PPARγ in TAMs, while inhibiting the relative protein expression of p-SYK, NOX2, and NOX4. Additionally, CD47 can enhance the angiogenic and proliferative abilities of Huh-7 cells and promote the polarization of TAMs to the M2 phenotype. In vivo experiments demonstrated that CD47-KD significantly inhibited tumour growth. Further co-culture experiments revealed that SHP2 overexpression enhanced the suppression of tumour growth, whereas SHP2 knockdown promoted tumour growth; concurrently knocking down both SHP2 and SYK reinstated tumour growth inhibition. CD47 promotes tumour-associated macrophage polarisation towards the M2 phenotype via the SHP2/SYK/ROS/SIRT1 axis, thereby exacerbating hepatocellular carcinoma progression.

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