Dynamin 3 Inhibits the Proliferation of Non-small-Cell Lung Cancer Cells by Suppressing c-MET–GBR2–STAT3 Complex Formation
Dynamin 3 (DNM3) has gained increased attention ever since its potential as a tumor suppressor was reported. However, its action in lung cancer (LC) is undefined. In this study, the role of DNM3 in LC development was investigated. DNM3 expression was found to be downregulated in tumors of patients w...
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Frontiers Media S.A.
2021-08-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.641403/full |
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| author | Qiang Lu Yunfeng Ni Wuping Wang Lei Wang Tao Jiang Lei Shang |
| author_facet | Qiang Lu Yunfeng Ni Wuping Wang Lei Wang Tao Jiang Lei Shang |
| author_sort | Qiang Lu |
| collection | DOAJ |
| description | Dynamin 3 (DNM3) has gained increased attention ever since its potential as a tumor suppressor was reported. However, its action in lung cancer (LC) is undefined. In this study, the role of DNM3 in LC development was investigated. DNM3 expression was found to be downregulated in tumors of patients with LC, especially those with metastasis. The DNM3 downregulation enhanced the proliferative and metastatic ability of LC cells, whereas its upregulation had the opposite effects. In vivo xenograft experiments confirmed that lung tumors with lower DNM3 expression had higher growth and metastatic abilities. Mechanistic studies revealed that DNM3 interacts with growth factor receptor-bound protein 2 (GBR2), thereby interrupting tyrosine-protein kinase Met (c-MET)–GBR2–signal transducer and activator of transcription 3 (STAT3) complex formation, which suppressed STAT3 activation. Therefore, the absence of DNM3 frees GBR2 to activate STAT3, which regulates the expression of genes related to LC proliferation and metastasis (e.g., cyclin D1 and Snail family transcriptional repressor 1). Additionally, the c-MET inhibitor crizotinib effectively suppressed LC cell proliferation and migration in vitro and in vivo, even with DNM3 depleted. Therefore, our study has demonstrated the antitumor effect of DNM3 in LC and suggests that the inhibition of c-MET might be a promising strategy for treating those LC patients with low DNM3 expression. |
| format | Article |
| id | doaj-art-ef1adb7455be4e0a991a8c2cf77e2f0f |
| institution | OA Journals |
| issn | 2296-634X |
| language | English |
| publishDate | 2021-08-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj-art-ef1adb7455be4e0a991a8c2cf77e2f0f2025-08-20T02:31:04ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-08-01910.3389/fcell.2021.641403641403Dynamin 3 Inhibits the Proliferation of Non-small-Cell Lung Cancer Cells by Suppressing c-MET–GBR2–STAT3 Complex FormationQiang Lu0Yunfeng Ni1Wuping Wang2Lei Wang3Tao Jiang4Lei Shang5Department of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi’an, ChinaDepartment of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi’an, ChinaDepartment of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi’an, ChinaDepartment of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi’an, ChinaDepartment of Thoracic Surgery, Tangdu Hospital, The Air Force Military Medical University, Xi’an, ChinaThe Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Department of Health Statistics, School of Public Health, The Air Force Military Medical University, Xi’an, ChinaDynamin 3 (DNM3) has gained increased attention ever since its potential as a tumor suppressor was reported. However, its action in lung cancer (LC) is undefined. In this study, the role of DNM3 in LC development was investigated. DNM3 expression was found to be downregulated in tumors of patients with LC, especially those with metastasis. The DNM3 downregulation enhanced the proliferative and metastatic ability of LC cells, whereas its upregulation had the opposite effects. In vivo xenograft experiments confirmed that lung tumors with lower DNM3 expression had higher growth and metastatic abilities. Mechanistic studies revealed that DNM3 interacts with growth factor receptor-bound protein 2 (GBR2), thereby interrupting tyrosine-protein kinase Met (c-MET)–GBR2–signal transducer and activator of transcription 3 (STAT3) complex formation, which suppressed STAT3 activation. Therefore, the absence of DNM3 frees GBR2 to activate STAT3, which regulates the expression of genes related to LC proliferation and metastasis (e.g., cyclin D1 and Snail family transcriptional repressor 1). Additionally, the c-MET inhibitor crizotinib effectively suppressed LC cell proliferation and migration in vitro and in vivo, even with DNM3 depleted. Therefore, our study has demonstrated the antitumor effect of DNM3 in LC and suggests that the inhibition of c-MET might be a promising strategy for treating those LC patients with low DNM3 expression.https://www.frontiersin.org/articles/10.3389/fcell.2021.641403/fulldynamin 3lung cancernon-small-cell lung cancergrowth factor receptor-bound protein 2antitumor effect |
| spellingShingle | Qiang Lu Yunfeng Ni Wuping Wang Lei Wang Tao Jiang Lei Shang Dynamin 3 Inhibits the Proliferation of Non-small-Cell Lung Cancer Cells by Suppressing c-MET–GBR2–STAT3 Complex Formation Frontiers in Cell and Developmental Biology dynamin 3 lung cancer non-small-cell lung cancer growth factor receptor-bound protein 2 antitumor effect |
| title | Dynamin 3 Inhibits the Proliferation of Non-small-Cell Lung Cancer Cells by Suppressing c-MET–GBR2–STAT3 Complex Formation |
| title_full | Dynamin 3 Inhibits the Proliferation of Non-small-Cell Lung Cancer Cells by Suppressing c-MET–GBR2–STAT3 Complex Formation |
| title_fullStr | Dynamin 3 Inhibits the Proliferation of Non-small-Cell Lung Cancer Cells by Suppressing c-MET–GBR2–STAT3 Complex Formation |
| title_full_unstemmed | Dynamin 3 Inhibits the Proliferation of Non-small-Cell Lung Cancer Cells by Suppressing c-MET–GBR2–STAT3 Complex Formation |
| title_short | Dynamin 3 Inhibits the Proliferation of Non-small-Cell Lung Cancer Cells by Suppressing c-MET–GBR2–STAT3 Complex Formation |
| title_sort | dynamin 3 inhibits the proliferation of non small cell lung cancer cells by suppressing c met gbr2 stat3 complex formation |
| topic | dynamin 3 lung cancer non-small-cell lung cancer growth factor receptor-bound protein 2 antitumor effect |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.641403/full |
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