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

研究成果: Contribution to journalArticle査読

抄録

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.

本文言語英語
ページ(範囲)1475-1483
ページ数9
ジャーナルLaboratory Investigation
101
11
DOI
出版ステータス出版済み - 11 2021

All Science Journal Classification (ASJC) codes

  • 病理学および法医学
  • 分子生物学
  • 細胞生物学

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