MICA+ Tumor Cell Upregulated Macrophage-Secreted MMP9 via PROS1-AXL Axis to Induce Tumor Immune Escape in Advanced Hepatocellular Carcinoma (HCC)
Background: tumor-associated macrophages (TAMs) constitute a significant proportion of non-cancerous cells within the intricate tumor microenvironment (TME) of hepatocellular carcinoma (HCC). Understanding the communication between macrophages and tumor cells, as well as investigating potential sign...
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MDPI AG
2024-01-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/16/2/269 |
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| author | Qiulin Wu Xicai Li Yan Yang Jingquan Huang Ming Yao Jianjun Li Yubin Huang Xiaoyong Cai David A. Geller Yihe Yan |
| author_facet | Qiulin Wu Xicai Li Yan Yang Jingquan Huang Ming Yao Jianjun Li Yubin Huang Xiaoyong Cai David A. Geller Yihe Yan |
| author_sort | Qiulin Wu |
| collection | DOAJ |
| description | Background: tumor-associated macrophages (TAMs) constitute a significant proportion of non-cancerous cells within the intricate tumor microenvironment (TME) of hepatocellular carcinoma (HCC). Understanding the communication between macrophages and tumor cells, as well as investigating potential signaling pathways, holds promise for enhancing therapeutic responses in HCC. Methods: single-cell RNA-sequencing data and bulk RNA-sequencing data were derived from open source databases Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Through this analysis, we elucidated the interactions between MICA+ tumor cells and MMP9+ macrophages, primarily mediated via the PROS1-AXL axis in advanced HCC. Subsequently, we employed a range of experimental techniques including lentivirus infection, recombinant protein stimulation, and AXL inhibition experiments to validate these interactions and unravel the underlying mechanisms. Results: we presented a single-cell atlas of advanced HCC, highlighting the expression patterns of MICA and MMP9 in tumor cells and macrophages, respectively. Activation of the interferon gamma (IFN-γ) signaling pathway was observed in MICA+ tumor cells and MMP9+ macrophages. We identified the existence of an interaction between MICA+ tumor cells and MMP9+ macrophages mediated via the PROS1-AXL axis. Additionally, we found MMP9+ macrophages had a positive correlation with M2-like macrophages. Subsequently, experiments validated that DNA damage not only induced MICA expression in tumor cells via IRF1, but also upregulated PROS1 levels in HCC cells, stimulating macrophages to secrete MMP9. Consequently, MMP9 led to the proteolysis of MICA. Conclusion: MICA+ HCC cells secreted PROS1, which upregulated MMP9 expression in macrophages through AXL receptors. The increased MMP9 activity resulted in the proteolytic shedding of MICA, leading to the release of soluble MICA (sMICA) and the subsequent facilitation of tumor immune escape. |
| first_indexed | 2024-03-08T11:03:20Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-08T11:03:20Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-73ee79ef33724234bd39064469ee37622024-01-26T15:34:40ZengMDPI AGCancers2072-66942024-01-0116226910.3390/cancers16020269MICA+ Tumor Cell Upregulated Macrophage-Secreted MMP9 via PROS1-AXL Axis to Induce Tumor Immune Escape in Advanced Hepatocellular Carcinoma (HCC)Qiulin Wu0Xicai Li1Yan Yang2Jingquan Huang3Ming Yao4Jianjun Li5Yubin Huang6Xiaoyong Cai7David A. Geller8Yihe Yan9Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, ChinaDepartment of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, ChinaDepartment of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, ChinaDepartment of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, ChinaDepartment of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, ChinaDepartment of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, ChinaDepartment of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, ChinaDepartment of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, ChinaThomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15260, USADepartment of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, ChinaBackground: tumor-associated macrophages (TAMs) constitute a significant proportion of non-cancerous cells within the intricate tumor microenvironment (TME) of hepatocellular carcinoma (HCC). Understanding the communication between macrophages and tumor cells, as well as investigating potential signaling pathways, holds promise for enhancing therapeutic responses in HCC. Methods: single-cell RNA-sequencing data and bulk RNA-sequencing data were derived from open source databases Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Through this analysis, we elucidated the interactions between MICA+ tumor cells and MMP9+ macrophages, primarily mediated via the PROS1-AXL axis in advanced HCC. Subsequently, we employed a range of experimental techniques including lentivirus infection, recombinant protein stimulation, and AXL inhibition experiments to validate these interactions and unravel the underlying mechanisms. Results: we presented a single-cell atlas of advanced HCC, highlighting the expression patterns of MICA and MMP9 in tumor cells and macrophages, respectively. Activation of the interferon gamma (IFN-γ) signaling pathway was observed in MICA+ tumor cells and MMP9+ macrophages. We identified the existence of an interaction between MICA+ tumor cells and MMP9+ macrophages mediated via the PROS1-AXL axis. Additionally, we found MMP9+ macrophages had a positive correlation with M2-like macrophages. Subsequently, experiments validated that DNA damage not only induced MICA expression in tumor cells via IRF1, but also upregulated PROS1 levels in HCC cells, stimulating macrophages to secrete MMP9. Consequently, MMP9 led to the proteolysis of MICA. Conclusion: MICA+ HCC cells secreted PROS1, which upregulated MMP9 expression in macrophages through AXL receptors. The increased MMP9 activity resulted in the proteolytic shedding of MICA, leading to the release of soluble MICA (sMICA) and the subsequent facilitation of tumor immune escape.https://www.mdpi.com/2072-6694/16/2/269HCCMICAPROS1AXLMMP9macrophage |
| spellingShingle | Qiulin Wu Xicai Li Yan Yang Jingquan Huang Ming Yao Jianjun Li Yubin Huang Xiaoyong Cai David A. Geller Yihe Yan MICA+ Tumor Cell Upregulated Macrophage-Secreted MMP9 via PROS1-AXL Axis to Induce Tumor Immune Escape in Advanced Hepatocellular Carcinoma (HCC) Cancers HCC MICA PROS1 AXL MMP9 macrophage |
| title | MICA+ Tumor Cell Upregulated Macrophage-Secreted MMP9 via PROS1-AXL Axis to Induce Tumor Immune Escape in Advanced Hepatocellular Carcinoma (HCC) |
| title_full | MICA+ Tumor Cell Upregulated Macrophage-Secreted MMP9 via PROS1-AXL Axis to Induce Tumor Immune Escape in Advanced Hepatocellular Carcinoma (HCC) |
| title_fullStr | MICA+ Tumor Cell Upregulated Macrophage-Secreted MMP9 via PROS1-AXL Axis to Induce Tumor Immune Escape in Advanced Hepatocellular Carcinoma (HCC) |
| title_full_unstemmed | MICA+ Tumor Cell Upregulated Macrophage-Secreted MMP9 via PROS1-AXL Axis to Induce Tumor Immune Escape in Advanced Hepatocellular Carcinoma (HCC) |
| title_short | MICA+ Tumor Cell Upregulated Macrophage-Secreted MMP9 via PROS1-AXL Axis to Induce Tumor Immune Escape in Advanced Hepatocellular Carcinoma (HCC) |
| title_sort | mica tumor cell upregulated macrophage secreted mmp9 via pros1 axl axis to induce tumor immune escape in advanced hepatocellular carcinoma hcc |
| topic | HCC MICA PROS1 AXL MMP9 macrophage |
| url | https://www.mdpi.com/2072-6694/16/2/269 |
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