Oral malignant melanoma, which frequently invades the hard palate or maxillary bone, is extremely rare and has a poor prognosis. Bone morphogenetic protein (BMP) is abundantly expressed in bone matrix and is highly expressed in malignant melanoma, inducing an aggressive phenotype. We examined the role of BMP signaling in the acquisition of an aggressive phenotype in melanoma cells in vitro and in vivo. In five cases, immunohistochemistry indicated the phosphorylation of Smad1/5 (p-Smad1/5) in the nuclei of melanoma cells. In the B16 mouse and A2058 human melanoma cell lines, BMP2, BMP4, or BMP7 induces morphological changes accompanied by the downregulation of E-cadherin, and the upregulation of N-cadherin and Snail, markers of epithelial–mesenchymal transition (EMT). BMP2 also stimulates cell invasion by increasing matrix metalloproteinase activity in B16 cells. These effects were canceled by the addition of LDN193189, a specific inhibitor of Smad1/5 signaling. In vivo, the injection of B16 cells expressing constitutively activated ALK3 enhanced zygoma destruction in comparison to empty B16 cells by increasing osteoclast numbers. These results suggest that the activation of BMP signaling induces EMT, thus driving the acquisition of an aggressive phenotype in malignant melanoma.
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We thank Dr. Takenobu Katagiri (Saitama Medical University, Saitama, Japan) for providing the d-WT4F-luciferase reporter and the V5-Tagged constitutively active form of BMPRIA (V5-CaALK3/pDEF). This work was supported by a research grant for the OBT Research Center from Kyushu University (to E.J.), and Fukuoka Public Health Promotion Organization Cancer Research Fund (to J.G.)
The authors declare no competing interests.
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All experimental procedures conducted in this study were reviewed and approved by the Kyushu University Research Ethics Committee (approval numbers 27–362 and 30–235), and by the Council on Animal Care and Use Committee of Kyushu University (approval number A30-362).
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Gao, J., Muroya, R., Huang, F. et al. Bone morphogenetic protein induces bone invasion of melanoma by epithelial–mesenchymal transition via the Smad1/5 signaling pathway. Lab Invest (2021). https://doi.org/10.1038/s41374-021-00661-y