ADAMTS16 drives epithelial-mesenchymal transition and metastasis through a feedback loop upon TGF-β1 activation in lung adenocarcinoma
Abstract Lung adenocarcinoma (LUAD) is the major subtype of lung cancer. The poor prognosis of LUAD patients is attributed primarily to metastasis. ADAMTS16 is a crucial member of the ADAMTS family and is involved in tumor progression. However, its role and regulatory mechanism in LUAD remain unexpl...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-11-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-07226-z |
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| author | Lingyan Xiao Qian Li Shuaijun Chen Yongbiao Huang Li Ma Yuan Wang Junjie Chen Jun Zhang Andong Liu Xianglin Yuan Yuanhui Liu Bo Liu |
| author_facet | Lingyan Xiao Qian Li Shuaijun Chen Yongbiao Huang Li Ma Yuan Wang Junjie Chen Jun Zhang Andong Liu Xianglin Yuan Yuanhui Liu Bo Liu |
| author_sort | Lingyan Xiao |
| collection | DOAJ |
| description | Abstract Lung adenocarcinoma (LUAD) is the major subtype of lung cancer. The poor prognosis of LUAD patients is attributed primarily to metastasis. ADAMTS16 is a crucial member of the ADAMTS family and is involved in tumor progression. However, its role and regulatory mechanism in LUAD remain unexplored. In this study, ADAMTS16 was identified as a crucial oncogene and survival predictor in LUAD via analyses of public datasets. Clinical specimens and tissue microarrays confirmed the differential expression and prognostic value of ADAMTS16 in LUAD patients. Transcriptome data and in vitro experiments demonstrated that ADAMTS16 was positively associated with epithelial-mesenchymal transition (EMT) and the migration abilities of LUAD cells. Knockdown of ADAMTS16 attenuated lung and pleural metastasis in an animal model. Mechanistically, the results of the enzyme-linked immunosorbent assay (ELISA) and western blot (WB) suggested that ADAMTS16 activated the TGF-β signaling pathway by facilitating the conversion of LAP-TGF-β1 to active TGF-β1. Co-Immunoprecipitation (co-IP) indicated an interaction between ADAMTS16 and LAP-TGF-β1. Inhibition of ADAMTS16 impaired EMT and aggressiveness of LUAD cells, while treatment with recombinant TGF-β1 reversed this inhibition. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays indicated that SOX4 acted as a transcriptional activator of ADAMTS16 and that TGF-β1 regulated the expression of ADAMTS16 by increasing the binding of SOX4 to the promoter of ADAMTS16. Suppressing the TGF-β signaling pathway inhibited ADAMTS16 expression, EMT, and lung metastasis, whereas overexpressing SOX4 reversed this inhibition. Therefore, ADAMTS16 forms a positive feedback loop with the TGF-β1/SOX4 axis to regulate EMT and metastasis, and disruption of this feedback loop inhibits tumor progression. These findings underscore the potential of ADAMTS16 as a prognostic biomarker and therapeutic target in LUAD and offer novel insight into the mechanism of EMT and metastasis. |
| format | Article |
| id | doaj-art-1477844ff33442738b27fc6537ff1017 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-1477844ff33442738b27fc6537ff10172024-11-17T12:51:06ZengNature Publishing GroupCell Death and Disease2041-48892024-11-01151111410.1038/s41419-024-07226-zADAMTS16 drives epithelial-mesenchymal transition and metastasis through a feedback loop upon TGF-β1 activation in lung adenocarcinomaLingyan Xiao0Qian Li1Shuaijun Chen2Yongbiao Huang3Li Ma4Yuan Wang5Junjie Chen6Jun Zhang7Andong Liu8Xianglin Yuan9Yuanhui Liu10Bo Liu11Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Pathology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Human Anatomy, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract Lung adenocarcinoma (LUAD) is the major subtype of lung cancer. The poor prognosis of LUAD patients is attributed primarily to metastasis. ADAMTS16 is a crucial member of the ADAMTS family and is involved in tumor progression. However, its role and regulatory mechanism in LUAD remain unexplored. In this study, ADAMTS16 was identified as a crucial oncogene and survival predictor in LUAD via analyses of public datasets. Clinical specimens and tissue microarrays confirmed the differential expression and prognostic value of ADAMTS16 in LUAD patients. Transcriptome data and in vitro experiments demonstrated that ADAMTS16 was positively associated with epithelial-mesenchymal transition (EMT) and the migration abilities of LUAD cells. Knockdown of ADAMTS16 attenuated lung and pleural metastasis in an animal model. Mechanistically, the results of the enzyme-linked immunosorbent assay (ELISA) and western blot (WB) suggested that ADAMTS16 activated the TGF-β signaling pathway by facilitating the conversion of LAP-TGF-β1 to active TGF-β1. Co-Immunoprecipitation (co-IP) indicated an interaction between ADAMTS16 and LAP-TGF-β1. Inhibition of ADAMTS16 impaired EMT and aggressiveness of LUAD cells, while treatment with recombinant TGF-β1 reversed this inhibition. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays indicated that SOX4 acted as a transcriptional activator of ADAMTS16 and that TGF-β1 regulated the expression of ADAMTS16 by increasing the binding of SOX4 to the promoter of ADAMTS16. Suppressing the TGF-β signaling pathway inhibited ADAMTS16 expression, EMT, and lung metastasis, whereas overexpressing SOX4 reversed this inhibition. Therefore, ADAMTS16 forms a positive feedback loop with the TGF-β1/SOX4 axis to regulate EMT and metastasis, and disruption of this feedback loop inhibits tumor progression. These findings underscore the potential of ADAMTS16 as a prognostic biomarker and therapeutic target in LUAD and offer novel insight into the mechanism of EMT and metastasis.https://doi.org/10.1038/s41419-024-07226-z |
| spellingShingle | Lingyan Xiao Qian Li Shuaijun Chen Yongbiao Huang Li Ma Yuan Wang Junjie Chen Jun Zhang Andong Liu Xianglin Yuan Yuanhui Liu Bo Liu ADAMTS16 drives epithelial-mesenchymal transition and metastasis through a feedback loop upon TGF-β1 activation in lung adenocarcinoma Cell Death and Disease |
| title | ADAMTS16 drives epithelial-mesenchymal transition and metastasis through a feedback loop upon TGF-β1 activation in lung adenocarcinoma |
| title_full | ADAMTS16 drives epithelial-mesenchymal transition and metastasis through a feedback loop upon TGF-β1 activation in lung adenocarcinoma |
| title_fullStr | ADAMTS16 drives epithelial-mesenchymal transition and metastasis through a feedback loop upon TGF-β1 activation in lung adenocarcinoma |
| title_full_unstemmed | ADAMTS16 drives epithelial-mesenchymal transition and metastasis through a feedback loop upon TGF-β1 activation in lung adenocarcinoma |
| title_short | ADAMTS16 drives epithelial-mesenchymal transition and metastasis through a feedback loop upon TGF-β1 activation in lung adenocarcinoma |
| title_sort | adamts16 drives epithelial mesenchymal transition and metastasis through a feedback loop upon tgf β1 activation in lung adenocarcinoma |
| url | https://doi.org/10.1038/s41419-024-07226-z |
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