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CCL4 Stimulates Cell Migration in Human Osteosarcoma via the mir-3927-3p/Integrin αvβ3 Axis

by 1,2, 3,†, 4,†, 5,6, 1,2,* and 1,7,8,9,10,*
1
School of Medicine, China Medical University, Taichung 404022, Taiwan
2
Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 404332, Taiwan
3
School of Chinese Medicine, China Medical University, Taichung 406040, Taiwan
4
Department of Medical Research, Chung Shan Medical University, Taichung 40201, Taiwan
5
Department of Sports Medicine, College of Health Care, China Medical University, Taichung 404022, Taiwan
6
Department of Orthopedic Surgery, China Medical University Beigang Hospital, Yunlin 651012, Taiwan
7
Graduate Institute of Basic Medical Science, China Medical University, Taichung 404022, Taiwan
8
Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404022, Taiwan
9
Chinese Medicine Research Center, China Medical University, Taichung 404022, Taiwan
10
Department of Biotechnology, College of Health Science, Asia University, Taichung 41354, Taiwan
*
Authors to whom correspondence should be addressed.
These authors have contributed equally to this work.
Academic Editor: Yousef Abu-Amer
Int. J. Mol. Sci. 2021, 22(23), 12737; https://doi.org/10.3390/ijms222312737
Received: 28 October 2021 / Revised: 18 November 2021 / Accepted: 23 November 2021 / Published: 25 November 2021
(This article belongs to the Special Issue Molecular Biology in Bone Tumors)
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. View Full-Text
Keywords: CCL4; integrin; miR-3927-3p; metastasis; osteosarcoma CCL4; integrin; miR-3927-3p; metastasis; osteosarcoma
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MDPI and ACS Style

Tsai, H.-C.; Lai, Y.-Y.; Hsu, H.-C.; Fong, Y.-C.; Lien, M.-Y.; Tang, C.-H. CCL4 Stimulates Cell Migration in Human Osteosarcoma via the mir-3927-3p/Integrin αvβ3 Axis. Int. J. Mol. Sci. 2021, 22, 12737. https://doi.org/10.3390/ijms222312737

AMA Style

Tsai H-C, Lai Y-Y, Hsu H-C, Fong Y-C, Lien M-Y, Tang C-H. CCL4 Stimulates Cell Migration in Human Osteosarcoma via the mir-3927-3p/Integrin αvβ3 Axis. International Journal of Molecular Sciences. 2021; 22(23):12737. https://doi.org/10.3390/ijms222312737

Chicago/Turabian Style

Tsai, Hsiao-Chi, Yan-You Lai, Hsuan-Chih Hsu, Yi-Chin Fong, Ming-Yu Lien, and Chih-Hsin Tang. 2021. "CCL4 Stimulates Cell Migration in Human Osteosarcoma via the mir-3927-3p/Integrin αvβ3 Axis" International Journal of Molecular Sciences 22, no. 23: 12737. https://doi.org/10.3390/ijms222312737

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