Semaphorin 4D promotes bone invasion in head and neck squamous cell carcinoma

Hiroyuki Takada, Soichiro Ibaragi, Takanori Eguchi, Tatsuo Okui, Kyoichi Obata, Masanori Masui, Ayaka Morisawa, Kiyofumi Takabatake, Hotaka Kawai, Norie Yoshioka, Nur Mohammad Monsur Hassan, Tsuyoshi Shimo, Guo Fu Hu, Hitoshi Nagatsuka, Akira Sasaki

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)


Head and neck squamous cell carcinomas (HNSCCs) frequently invade the bones of the facial skeleton. Semaphorin 4D (Sema4D) is an axon guidance molecule produced by oligodendrocytes. Sema4D was also identified in the bone microenvironment and many cancer tissues including HNSCC. To date, however, the role of Sema4D in cancer-associated bone disease is still unknown. This is the first study to demonstrate the role of Sema4D in bone invasion of cancer. In the clinical tissue samples of bone lesion of HNSCC, Sema4D was detected at high levels, and its expression was correlated with insulin-like growth factor-I (IGF-I) expression. In vitro experiments showed that IGF-I regulates Sema4D expression and Sema4D increased proliferation, migration and invasion in HNSCC cells. Sema4D also regulated the expression of receptor activator of nuclear factor κβ ligand (RANKL) in osteoblasts, and this stimulated osteoclastgenesis. Fur thermore, knockdown of Sema4D in HNSCC cells inhibited tumor growth and decreased the number of osteoclasts in a mouse xenograft model. Taken together, IGF-I-driven production of Sema4D in HNSCCs promotes osteoclastogenesis and bone invasion.

Original languageEnglish
Pages (from-to)625-632
Number of pages8
JournalInternational journal of oncology
Issue number2
Publication statusPublished - Aug 2017


  • Bone invasion
  • Head and neck squamous cell carcinoma
  • Insulin-like growth factor-I
  • Osteoclastogenesis
  • Plexin-B1
  • Semaphorin 4D

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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