Bone morphogenetic protein induces bone invasion of melanoma by epithelial–mesenchymal transition via the Smad1/5 signaling pathway

Jing Gao, Ryusuke Muroya, Fei Huang, Kengo Nagata, Masashi Shin, Ryoko Nagano, Yudai Tajiri, Shinsuke Fujii, Takayoshi Yamaza, Kazuhiro Aoki, Yukihiko Tamura, Mayuko Inoue, Sakura Chishaki, Toshio Kukita, Koji Okabe, Miho Matsuda, Yoshihide Mori, Tamotsu Kiyoshima, Eijiro Jimi

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1475-1483
Number of pages9
JournalLaboratory Investigation
Volume101
Issue number11
DOIs
Publication statusPublished - Nov 2021

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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