CCL4 Stimulates Cell Migration in Human Osteosarcoma via the mir-3927-3p/Integrin αvβ3 Axis
Osteosarcoma is the most common type of primary malignant bone cancer, and it is associated with high rates of pulmonary metastasis. Integrin αvβ3 is critical for osteosarcoma cell migratory and invasive abilities. Chemokine (C-C motif) ligand 4 (CCL4) has diverse effects on different cancer cells t...
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MDPI AG
2021-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/23/12737 |
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| author | Hsiao-Chi Tsai Yan-You Lai Hsuan-Chih Hsu Yi-Chin Fong Ming-Yu Lien Chih-Hsin Tang |
| author_facet | Hsiao-Chi Tsai Yan-You Lai Hsuan-Chih Hsu Yi-Chin Fong Ming-Yu Lien Chih-Hsin Tang |
| author_sort | Hsiao-Chi Tsai |
| collection | DOAJ |
| description | Osteosarcoma is the most common type of primary malignant bone cancer, and it is associated with high rates of pulmonary metastasis. Integrin αvβ3 is critical for osteosarcoma cell migratory and invasive abilities. Chemokine (C-C motif) ligand 4 (CCL4) has diverse effects on different cancer cells through its interaction with its specific receptor, C-C chemokine receptor type 5 (CCR5). Analysis of mRNA expression in human osteosarcoma tissue identified upregulated levels of CCL4, integrin αv and β3 expression. Similarly, an analysis of records from the Gene Expression Omnibus (GEO) dataset showed that CCL4 was upregulated in human osteosarcoma tissue. Importantly, the expression of both CCL4 and integrin αvβ3 correlated positively with osteosarcoma clinical stages and lung metastasis. Analysis of osteosarcoma cell lines identified that CCL4 promotes integrin αvβ3 expression and cell migration by activating the focal adhesion kinase (FAK), protein kinase B (AKT), and hypoxia inducible factor 1 subunit alpha (HIF-1α) signaling pathways, which can downregulate microRNA-3927-3p expression. Pharmacological inhibition of CCR5 by maraviroc (MVC) prevented increases in integrin αvβ3 expression and cell migration. This study is the first to implicate CCL4 as a potential target in the treatment of metastatic osteosarcoma. |
| first_indexed | 2024-03-10T04:53:34Z |
| format | Article |
| id | doaj.art-af030fe5b1b54bf7a81b12b42bb35c51 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T04:53:34Z |
| publishDate | 2021-11-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-af030fe5b1b54bf7a81b12b42bb35c512023-11-23T02:27:15ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-11-0122231273710.3390/ijms222312737CCL4 Stimulates Cell Migration in Human Osteosarcoma via the mir-3927-3p/Integrin αvβ3 AxisHsiao-Chi Tsai0Yan-You Lai1Hsuan-Chih Hsu2Yi-Chin Fong3Ming-Yu Lien4Chih-Hsin Tang5School of Medicine, China Medical University, Taichung 404022, TaiwanSchool of Chinese Medicine, China Medical University, Taichung 406040, TaiwanDepartment of Medical Research, Chung Shan Medical University, Taichung 40201, TaiwanDepartment of Sports Medicine, College of Health Care, China Medical University, Taichung 404022, TaiwanSchool of Medicine, China Medical University, Taichung 404022, TaiwanSchool of Medicine, China Medical University, Taichung 404022, TaiwanOsteosarcoma is the most common type of primary malignant bone cancer, and it is associated with high rates of pulmonary metastasis. Integrin αvβ3 is critical for osteosarcoma cell migratory and invasive abilities. Chemokine (C-C motif) ligand 4 (CCL4) has diverse effects on different cancer cells through its interaction with its specific receptor, C-C chemokine receptor type 5 (CCR5). Analysis of mRNA expression in human osteosarcoma tissue identified upregulated levels of CCL4, integrin αv and β3 expression. Similarly, an analysis of records from the Gene Expression Omnibus (GEO) dataset showed that CCL4 was upregulated in human osteosarcoma tissue. Importantly, the expression of both CCL4 and integrin αvβ3 correlated positively with osteosarcoma clinical stages and lung metastasis. Analysis of osteosarcoma cell lines identified that CCL4 promotes integrin αvβ3 expression and cell migration by activating the focal adhesion kinase (FAK), protein kinase B (AKT), and hypoxia inducible factor 1 subunit alpha (HIF-1α) signaling pathways, which can downregulate microRNA-3927-3p expression. Pharmacological inhibition of CCR5 by maraviroc (MVC) prevented increases in integrin αvβ3 expression and cell migration. This study is the first to implicate CCL4 as a potential target in the treatment of metastatic osteosarcoma.https://www.mdpi.com/1422-0067/22/23/12737CCL4integrinmiR-3927-3pmetastasisosteosarcoma |
| spellingShingle | Hsiao-Chi Tsai Yan-You Lai Hsuan-Chih Hsu Yi-Chin Fong Ming-Yu Lien Chih-Hsin Tang CCL4 Stimulates Cell Migration in Human Osteosarcoma via the mir-3927-3p/Integrin αvβ3 Axis International Journal of Molecular Sciences CCL4 integrin miR-3927-3p metastasis osteosarcoma |
| title | CCL4 Stimulates Cell Migration in Human Osteosarcoma via the mir-3927-3p/Integrin αvβ3 Axis |
| title_full | CCL4 Stimulates Cell Migration in Human Osteosarcoma via the mir-3927-3p/Integrin αvβ3 Axis |
| title_fullStr | CCL4 Stimulates Cell Migration in Human Osteosarcoma via the mir-3927-3p/Integrin αvβ3 Axis |
| title_full_unstemmed | CCL4 Stimulates Cell Migration in Human Osteosarcoma via the mir-3927-3p/Integrin αvβ3 Axis |
| title_short | CCL4 Stimulates Cell Migration in Human Osteosarcoma via the mir-3927-3p/Integrin αvβ3 Axis |
| title_sort | ccl4 stimulates cell migration in human osteosarcoma via the mir 3927 3p integrin αvβ3 axis |
| topic | CCL4 integrin miR-3927-3p metastasis osteosarcoma |
| url | https://www.mdpi.com/1422-0067/22/23/12737 |
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