GP73-mediated secretion of PKM2 and GP73 promotes angiogenesis and M2-like macrophage polarization in hepatocellular carcinoma
Abstract Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Abnormally high expression of Golgi protein 73 (GP73) and pyruvate kinase M2 (PKM2) is intimately associated with HCC progression. However, as secreted proteins, the role of their extracellular secretions in HCC prog...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-02-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07391-9 |
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| author | Shujie Wang Tongjia Zhang Yue Zhou Zitao Jiao Kejia Lu Xinyi Liu Wei Jiang Zhe Yang Hui Li Xiaowei Zhang |
| author_facet | Shujie Wang Tongjia Zhang Yue Zhou Zitao Jiao Kejia Lu Xinyi Liu Wei Jiang Zhe Yang Hui Li Xiaowei Zhang |
| author_sort | Shujie Wang |
| collection | DOAJ |
| description | Abstract Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Abnormally high expression of Golgi protein 73 (GP73) and pyruvate kinase M2 (PKM2) is intimately associated with HCC progression. However, as secreted proteins, the role of their extracellular secretions in HCC progression remains unclear. Here, we demonstrated that the expression of extracellular GP73 was positively correlated with extracellular PKM2. GP73 interacted with PKM2 to promote SUMO1 modification of PKM2, which in turn enhanced the interaction of GP73 and PKM2. This process continuously promoted the transfer of PKM2 from the cytoplasm to the membrane in HCC cells, and finally secretion. Extracellular PKM2 and GP73 synergistically promoted angiogenesis and polarization of M2-type macrophages, thereby leading to malignant progression and sorafenib resistance in HCC. Sorafenib combined with shikonin, a specific inhibitor of PKM2, has a strong anti-tumor effect. This study reveals the role of GP73 in enhancing PKM2 and GP73 secretion in promoting HCC progression, providing a theoretical basis and drug targets for HCC therapy. |
| format | Article |
| id | doaj-art-f29cbbb40f134813b6234ff908164513 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Publishing Group |
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| series | Cell Death and Disease |
| spelling | doaj-art-f29cbbb40f134813b6234ff9081645132025-02-09T12:56:40ZengNature Publishing GroupCell Death and Disease2041-48892025-02-0116111710.1038/s41419-025-07391-9GP73-mediated secretion of PKM2 and GP73 promotes angiogenesis and M2-like macrophage polarization in hepatocellular carcinomaShujie Wang0Tongjia Zhang1Yue Zhou2Zitao Jiao3Kejia Lu4Xinyi Liu5Wei Jiang6Zhe Yang7Hui Li8Xiaowei Zhang9Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science CenterDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science CenterDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science CenterDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science CenterDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science CenterDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science CenterDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science CenterDepartment of Pathology, The First Affiliated Hospital of Kunming Medical UniversityDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science CenterDepartment of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science CenterAbstract Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Abnormally high expression of Golgi protein 73 (GP73) and pyruvate kinase M2 (PKM2) is intimately associated with HCC progression. However, as secreted proteins, the role of their extracellular secretions in HCC progression remains unclear. Here, we demonstrated that the expression of extracellular GP73 was positively correlated with extracellular PKM2. GP73 interacted with PKM2 to promote SUMO1 modification of PKM2, which in turn enhanced the interaction of GP73 and PKM2. This process continuously promoted the transfer of PKM2 from the cytoplasm to the membrane in HCC cells, and finally secretion. Extracellular PKM2 and GP73 synergistically promoted angiogenesis and polarization of M2-type macrophages, thereby leading to malignant progression and sorafenib resistance in HCC. Sorafenib combined with shikonin, a specific inhibitor of PKM2, has a strong anti-tumor effect. This study reveals the role of GP73 in enhancing PKM2 and GP73 secretion in promoting HCC progression, providing a theoretical basis and drug targets for HCC therapy.https://doi.org/10.1038/s41419-025-07391-9 |
| spellingShingle | Shujie Wang Tongjia Zhang Yue Zhou Zitao Jiao Kejia Lu Xinyi Liu Wei Jiang Zhe Yang Hui Li Xiaowei Zhang GP73-mediated secretion of PKM2 and GP73 promotes angiogenesis and M2-like macrophage polarization in hepatocellular carcinoma Cell Death and Disease |
| title | GP73-mediated secretion of PKM2 and GP73 promotes angiogenesis and M2-like macrophage polarization in hepatocellular carcinoma |
| title_full | GP73-mediated secretion of PKM2 and GP73 promotes angiogenesis and M2-like macrophage polarization in hepatocellular carcinoma |
| title_fullStr | GP73-mediated secretion of PKM2 and GP73 promotes angiogenesis and M2-like macrophage polarization in hepatocellular carcinoma |
| title_full_unstemmed | GP73-mediated secretion of PKM2 and GP73 promotes angiogenesis and M2-like macrophage polarization in hepatocellular carcinoma |
| title_short | GP73-mediated secretion of PKM2 and GP73 promotes angiogenesis and M2-like macrophage polarization in hepatocellular carcinoma |
| title_sort | gp73 mediated secretion of pkm2 and gp73 promotes angiogenesis and m2 like macrophage polarization in hepatocellular carcinoma |
| url | https://doi.org/10.1038/s41419-025-07391-9 |
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