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<p>Tumor-associated macrophages (TAMs) primarily exhibit a protumor M2-like phenotype, which substantially affects hepatocellular carcinoma (HCC) progression via their immunosuppressive properties. The oncoprotein high-mobility gene group A2 (HMGA2) is abnormally overexpressed in HCC. However, the mechanisms by which HMGA2 regulates the HCC tumor microenvironment remain incompletely understood. The relative expression levels of HMGA2 in HCC tissues and adjacent peritumoral tissues were determined by quantitative real-time polymerase chain reaction (qRT‒PCR), Western blotting, and immunohistochemistry (IHC). The biological function of HMGA2 was determined by CCK-8 and Transwell migration assays. In vitro coculture assays were used to investigate the role of HMGA2 in the migration and polarization of macrophages in HCC cells. The in vivo tumor xenograft model to investigate the impact of HMGA2 loss-of-function on tumor growth and TAM infiltration. The mRNA and protein expression levels of HMGA2 were increased in HCC tissues and cell lines. Overexpression of HMGA2 increased the proliferation of HCC cells while promoting HCC cell migration. HMGA2 expression was positively correlated with CD68 + and CD163 + expression, and elevated M2 macrophages in HCC patients were significantly associated with poor prognosis. Moreover, we found that HMGA2 in HCC cells facilitated macrophage recruitment and M2 polarization by inducing CCL2 secretion by upregulating NOTCH1, thus promoting macrophage recruitment in vitro. Finally, knockdown of HMGA2 suppressed HCC growth and reduced M2-TAM infiltration in vivo. This research indicated that HMGA2 overexpression in HCC cells promotes the recruitment of macrophages and M2 polarization by mediating CCL2 secretion through Notch1 upregulation, thereby promoting HCC tumor immunosuppression.</p>

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HMGA2 promotes hepatocellular carcinoma progression by regulating tumor-associated macrophage via Notch1/CCL2 signaling

  • 期刊论文

  • 发表日期：

    2026年2月3日

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  • Zhaomin Xing,
  • Jingyu Xun,
  • Liang Deng

摘要

Tumor-associated macrophages (TAMs) primarily exhibit a protumor M2-like phenotype, which substantially affects hepatocellular carcinoma (HCC) progression via their immunosuppressive properties. The oncoprotein high-mobility gene group A2 (HMGA2) is abnormally overexpressed in HCC. However, the mechanisms by which HMGA2 regulates the HCC tumor microenvironment remain incompletely understood. The relative expression levels of HMGA2 in HCC tissues and adjacent peritumoral tissues were determined by quantitative real-time polymerase chain reaction (qRT‒PCR), Western blotting, and immunohistochemistry (IHC). The biological function of HMGA2 was determined by CCK-8 and Transwell migration assays. In vitro coculture assays were used to investigate the role of HMGA2 in the migration and polarization of macrophages in HCC cells. The in vivo tumor xenograft model to investigate the impact of HMGA2 loss-of-function on tumor growth and TAM infiltration. The mRNA and protein expression levels of HMGA2 were increased in HCC tissues and cell lines. Overexpression of HMGA2 increased the proliferation of HCC cells while promoting HCC cell migration. HMGA2 expression was positively correlated with CD68 + and CD163 + expression, and elevated M2 macrophages in HCC patients were significantly associated with poor prognosis. Moreover, we found that HMGA2 in HCC cells facilitated macrophage recruitment and M2 polarization by inducing CCL2 secretion by upregulating NOTCH1, thus promoting macrophage recruitment in vitro. Finally, knockdown of HMGA2 suppressed HCC growth and reduced M2-TAM infiltration in vivo. This research indicated that HMGA2 overexpression in HCC cells promotes the recruitment of macrophages and M2 polarization by mediating CCL2 secretion through Notch1 upregulation, thereby promoting HCC tumor immunosuppression.