Cancer Cell‐Derived Exosomal miR‐500a‐3p Modulates Hepatic Stellate Cell Activation and the Immunosuppressive Microenvironment
Abstract Hepatocellular carcinoma (HCC) mainly depends on liver fibrosis/cirrhosis, which is regulated by tumor cells and the tumor microenvironment (TME), and is a crucial factor in tumor progression. This study aimed to identify abnormally expressed miR‐500a‐3p in the hepatitis‐cirrhosis‐HCC pathw...
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Wiley
2025-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202404089 |
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| author | Yu Zhang Xin Li Huiyan Chen Jiawei Li Xiaohuan Guo Yilin Fang Linjie Chen Kaiqiang Li Yi Zhang Fei Kong Aodong Chen Jianxin Lyu Wei Zhang Zhen Wang |
| author_facet | Yu Zhang Xin Li Huiyan Chen Jiawei Li Xiaohuan Guo Yilin Fang Linjie Chen Kaiqiang Li Yi Zhang Fei Kong Aodong Chen Jianxin Lyu Wei Zhang Zhen Wang |
| author_sort | Yu Zhang |
| collection | DOAJ |
| description | Abstract Hepatocellular carcinoma (HCC) mainly depends on liver fibrosis/cirrhosis, which is regulated by tumor cells and the tumor microenvironment (TME), and is a crucial factor in tumor progression. This study aimed to identify abnormally expressed miR‐500a‐3p in the hepatitis‐cirrhosis‐HCC pathway and explored the roles of miR‐500a‐3p in HCC progression. A clinical cohort of patients with HCC is studied retrospectively. Subsequently, the role of miR‐500a‐3p transported by HCC exosomes in hepatic stellate cell (HSC) activation, hepatoma growth and invasion, and immune cell differentiation is determined by in vitro and in vivo experiments. In clinical tissues, miR‐500a‐3p is significantly enriched in HCC and cirrhosis tissues, and co‐expression of the immune marker CD4 or PD‐L1 significantly correlates with low survival rates in patients. Extracellular miR‐500a‐3p is taken up by HSC and PBMC, which promotes the secretion of the cytokines TGF‐β1 and IL‐10, increases PD‐L1 expression in HSC, and stabilizes PD‐1 expression in PBMC to affect the TME. Moreover, miR‐500a‐3p is associated with CD4+ T‐cell exhaustion and Treg differentiation and is significantly associated with increased tumorigenicity in in situ mouse HCC models. Mechanistically, HCC‐derived exosomal miR‐500a‐3p directly influences SOCS2 to regulate the JAK3/STAT5A/STAT5B signaling pathway. MiR‐500a‐3p promotes the growth and migration of HCC through the SOCS2/JAK3/STAT5A/STAT5B axis. |
| format | Article |
| id | doaj-art-8b1bdd22cef2440b986b054ed2792cce |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-8b1bdd22cef2440b986b054ed2792cce2025-01-13T15:29:43ZengWileyAdvanced Science2198-38442025-01-01122n/an/a10.1002/advs.202404089Cancer Cell‐Derived Exosomal miR‐500a‐3p Modulates Hepatic Stellate Cell Activation and the Immunosuppressive MicroenvironmentYu Zhang0Xin Li1Huiyan Chen2Jiawei Li3Xiaohuan Guo4Yilin Fang5Linjie Chen6Kaiqiang Li7Yi Zhang8Fei Kong9Aodong Chen10Jianxin Lyu11Wei Zhang12Zhen Wang13Cancer CenterDepartment of Gastroenterology Zhejiang Provincial People's Hospital (Affiliated People's Hospital) Hangzhou Medical College Hangzhou Zhejiang 310014 ChinaSchool of Ophthalmology and Optometry and Eye Hospital Wenzhou Medical University Wenzhou Zhejiang 325035 ChinaLaboratory Medicine Center Allergy Center Department of Transfusion Medicine Zhejiang Provincial People's Hospital (Affiliated People's Hospital) Hangzhou Medical College Hangzhou 310014 ChinaSchool of Ophthalmology and Optometry and Eye Hospital Wenzhou Medical University Wenzhou Zhejiang 325035 ChinaLaboratory Medicine Center Allergy Center Department of Transfusion Medicine Zhejiang Provincial People's Hospital (Affiliated People's Hospital) Hangzhou Medical College Hangzhou 310014 ChinaLaboratory Medicine Center Allergy Center Department of Transfusion Medicine Zhejiang Provincial People's Hospital (Affiliated People's Hospital) Hangzhou Medical College Hangzhou 310014 ChinaLaboratory Medicine Center Allergy Center Department of Transfusion Medicine Zhejiang Provincial People's Hospital (Affiliated People's Hospital) Hangzhou Medical College Hangzhou 310014 ChinaLaboratory Medicine Center Allergy Center Department of Transfusion Medicine Zhejiang Provincial People's Hospital (Affiliated People's Hospital) Hangzhou Medical College Hangzhou 310014 ChinaLaboratory Medicine Center Allergy Center Department of Transfusion Medicine Zhejiang Provincial People's Hospital (Affiliated People's Hospital) Hangzhou Medical College Hangzhou 310014 ChinaLaboratory Medicine Center Allergy Center Department of Transfusion Medicine Zhejiang Provincial People's Hospital (Affiliated People's Hospital) Hangzhou Medical College Hangzhou 310014 ChinaSchool of Ophthalmology and Optometry and Eye Hospital Wenzhou Medical University Wenzhou Zhejiang 325035 ChinaLaboratory Medicine Center Allergy Center Department of Transfusion Medicine Zhejiang Provincial People's Hospital (Affiliated People's Hospital) Hangzhou Medical College Hangzhou 310014 ChinaDepartment of General Surgery The second affiliated hospital of Zhejiang Chinese Medical University Hangzhou 310015 ChinaLaboratory Medicine Center Allergy Center Department of Transfusion Medicine Zhejiang Provincial People's Hospital (Affiliated People's Hospital) Hangzhou Medical College Hangzhou 310014 ChinaAbstract Hepatocellular carcinoma (HCC) mainly depends on liver fibrosis/cirrhosis, which is regulated by tumor cells and the tumor microenvironment (TME), and is a crucial factor in tumor progression. This study aimed to identify abnormally expressed miR‐500a‐3p in the hepatitis‐cirrhosis‐HCC pathway and explored the roles of miR‐500a‐3p in HCC progression. A clinical cohort of patients with HCC is studied retrospectively. Subsequently, the role of miR‐500a‐3p transported by HCC exosomes in hepatic stellate cell (HSC) activation, hepatoma growth and invasion, and immune cell differentiation is determined by in vitro and in vivo experiments. In clinical tissues, miR‐500a‐3p is significantly enriched in HCC and cirrhosis tissues, and co‐expression of the immune marker CD4 or PD‐L1 significantly correlates with low survival rates in patients. Extracellular miR‐500a‐3p is taken up by HSC and PBMC, which promotes the secretion of the cytokines TGF‐β1 and IL‐10, increases PD‐L1 expression in HSC, and stabilizes PD‐1 expression in PBMC to affect the TME. Moreover, miR‐500a‐3p is associated with CD4+ T‐cell exhaustion and Treg differentiation and is significantly associated with increased tumorigenicity in in situ mouse HCC models. Mechanistically, HCC‐derived exosomal miR‐500a‐3p directly influences SOCS2 to regulate the JAK3/STAT5A/STAT5B signaling pathway. MiR‐500a‐3p promotes the growth and migration of HCC through the SOCS2/JAK3/STAT5A/STAT5B axis.https://doi.org/10.1002/advs.202404089exosomehepatic stellate cellhepatocellular carcinomaT celltumor microenvironment |
| spellingShingle | Yu Zhang Xin Li Huiyan Chen Jiawei Li Xiaohuan Guo Yilin Fang Linjie Chen Kaiqiang Li Yi Zhang Fei Kong Aodong Chen Jianxin Lyu Wei Zhang Zhen Wang Cancer Cell‐Derived Exosomal miR‐500a‐3p Modulates Hepatic Stellate Cell Activation and the Immunosuppressive Microenvironment Advanced Science exosome hepatic stellate cell hepatocellular carcinoma T cell tumor microenvironment |
| title | Cancer Cell‐Derived Exosomal miR‐500a‐3p Modulates Hepatic Stellate Cell Activation and the Immunosuppressive Microenvironment |
| title_full | Cancer Cell‐Derived Exosomal miR‐500a‐3p Modulates Hepatic Stellate Cell Activation and the Immunosuppressive Microenvironment |
| title_fullStr | Cancer Cell‐Derived Exosomal miR‐500a‐3p Modulates Hepatic Stellate Cell Activation and the Immunosuppressive Microenvironment |
| title_full_unstemmed | Cancer Cell‐Derived Exosomal miR‐500a‐3p Modulates Hepatic Stellate Cell Activation and the Immunosuppressive Microenvironment |
| title_short | Cancer Cell‐Derived Exosomal miR‐500a‐3p Modulates Hepatic Stellate Cell Activation and the Immunosuppressive Microenvironment |
| title_sort | cancer cell derived exosomal mir 500a 3p modulates hepatic stellate cell activation and the immunosuppressive microenvironment |
| topic | exosome hepatic stellate cell hepatocellular carcinoma T cell tumor microenvironment |
| url | https://doi.org/10.1002/advs.202404089 |
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