HMGA1 Promotes Macrophage Recruitment via Activation of NF-κB-CCL2 Signaling in Hepatocellular Carcinoma
Background. Tumor-associated macrophages (TAMs) are known to generate an immune-suppressive tumor microenvironment (TME) and promote tumor progression. Hepatocellular carcinoma (HCC) is a devastating disease that evolves in the background of chronic inflammatory liver damage. In this study, we aimed...
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| Format: | Article |
| Language: | English |
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Wiley
2022-01-01
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| Series: | Journal of Immunology Research |
| Online Access: | http://dx.doi.org/10.1155/2022/4727198 |
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| author | Junming Chen Kang Ji Lingyan Gu Yu Fang Ming Pan Shuxia Tian |
| author_facet | Junming Chen Kang Ji Lingyan Gu Yu Fang Ming Pan Shuxia Tian |
| author_sort | Junming Chen |
| collection | DOAJ |
| description | Background. Tumor-associated macrophages (TAMs) are known to generate an immune-suppressive tumor microenvironment (TME) and promote tumor progression. Hepatocellular carcinoma (HCC) is a devastating disease that evolves in the background of chronic inflammatory liver damage. In this study, we aimed to uncover the mechanism by which HCC cells recruit macrophages into the TME. Methods. Bioinformatic analysis was performed to identify differentially expressed genes related to macrophage infiltration. An orthotopic HCC xenograft model was used to determine the role of macrophages in HCC tumor growth. Clodronate liposomes were used to delete macrophages. Western blotting analysis, quantitative real-time PCR, and enzyme-linked immunosorbent assay were performed to determine the underlying mechanisms. Results. The high mobility group A1 (HMGA1) gene was identified as a putative modulator of macrophage infiltration in HCC. Deletion of macrophages with clodronate liposomes significantly abrogated the tumor-promoting effects of HMGA1 on HCC growth. Mechanistically, HMGA1 can regulate the expression of C-C Motif Chemokine Ligand 2 (CCL2), also referred to as monocyte chemoattractant protein 1 (MCP1), which is responsible for macrophage recruitment. Moreover, NF-κB was required for HMGA1-mediated CCL2 expression. Pharmacological or genetic inhibition of NF-κB largely blocked CCL2 levels in HMGA1-overexpressing HCC cells. Conclusions. This study reveals HMGA1 as a crucial regulator of macrophage recruitment by activating NF-κB-CCL2 signaling, proves that HMGA1-induced HCC aggressiveness dependents on the macrophage, and provide an attractive target for therapeutic interventions in HCC. |
| format | Article |
| id | doaj-art-e8922358d54b42aa9f77d3d5be08e050 |
| institution | OA Journals |
| issn | 2314-7156 |
| language | English |
| publishDate | 2022-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Immunology Research |
| spelling | doaj-art-e8922358d54b42aa9f77d3d5be08e0502025-08-20T02:22:15ZengWileyJournal of Immunology Research2314-71562022-01-01202210.1155/2022/4727198HMGA1 Promotes Macrophage Recruitment via Activation of NF-κB-CCL2 Signaling in Hepatocellular CarcinomaJunming Chen0Kang Ji1Lingyan Gu2Yu Fang3Ming Pan4Shuxia Tian5Department of TCMDepartment of TCMDepartment of TCMDepartment of TCMDepartment of TCMDepartment of TCMBackground. Tumor-associated macrophages (TAMs) are known to generate an immune-suppressive tumor microenvironment (TME) and promote tumor progression. Hepatocellular carcinoma (HCC) is a devastating disease that evolves in the background of chronic inflammatory liver damage. In this study, we aimed to uncover the mechanism by which HCC cells recruit macrophages into the TME. Methods. Bioinformatic analysis was performed to identify differentially expressed genes related to macrophage infiltration. An orthotopic HCC xenograft model was used to determine the role of macrophages in HCC tumor growth. Clodronate liposomes were used to delete macrophages. Western blotting analysis, quantitative real-time PCR, and enzyme-linked immunosorbent assay were performed to determine the underlying mechanisms. Results. The high mobility group A1 (HMGA1) gene was identified as a putative modulator of macrophage infiltration in HCC. Deletion of macrophages with clodronate liposomes significantly abrogated the tumor-promoting effects of HMGA1 on HCC growth. Mechanistically, HMGA1 can regulate the expression of C-C Motif Chemokine Ligand 2 (CCL2), also referred to as monocyte chemoattractant protein 1 (MCP1), which is responsible for macrophage recruitment. Moreover, NF-κB was required for HMGA1-mediated CCL2 expression. Pharmacological or genetic inhibition of NF-κB largely blocked CCL2 levels in HMGA1-overexpressing HCC cells. Conclusions. This study reveals HMGA1 as a crucial regulator of macrophage recruitment by activating NF-κB-CCL2 signaling, proves that HMGA1-induced HCC aggressiveness dependents on the macrophage, and provide an attractive target for therapeutic interventions in HCC.http://dx.doi.org/10.1155/2022/4727198 |
| spellingShingle | Junming Chen Kang Ji Lingyan Gu Yu Fang Ming Pan Shuxia Tian HMGA1 Promotes Macrophage Recruitment via Activation of NF-κB-CCL2 Signaling in Hepatocellular Carcinoma Journal of Immunology Research |
| title | HMGA1 Promotes Macrophage Recruitment via Activation of NF-κB-CCL2 Signaling in Hepatocellular Carcinoma |
| title_full | HMGA1 Promotes Macrophage Recruitment via Activation of NF-κB-CCL2 Signaling in Hepatocellular Carcinoma |
| title_fullStr | HMGA1 Promotes Macrophage Recruitment via Activation of NF-κB-CCL2 Signaling in Hepatocellular Carcinoma |
| title_full_unstemmed | HMGA1 Promotes Macrophage Recruitment via Activation of NF-κB-CCL2 Signaling in Hepatocellular Carcinoma |
| title_short | HMGA1 Promotes Macrophage Recruitment via Activation of NF-κB-CCL2 Signaling in Hepatocellular Carcinoma |
| title_sort | hmga1 promotes macrophage recruitment via activation of nf κb ccl2 signaling in hepatocellular carcinoma |
| url | http://dx.doi.org/10.1155/2022/4727198 |
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