Department of Oral and Maxillofacial Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Kita-ku, Okayama, Japan.
Department of Dental Pharmacology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Kita-ku, Okayama, Japan.
Int J Oncol. 2017 Aug;51(2):625-632. doi: 10.3892/ijo.2017.4050. Epub 2017 Jun 21.
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. Furthermore, 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.
头颈部鳞状细胞癌（HNSCC）常侵犯面颅骨的骨骼。信号素 4D（Sema4D）是少突胶质细胞产生的轴突导向分子。Sema4D 也在骨微环境和许多癌症组织中被发现，包括 HNSCC。然而，到目前为止，Sema4D 在癌症相关骨病中的作用仍不清楚。这是第一项研究表明 Sema4D 在癌症骨侵袭中的作用。在 HNSCC 骨病变的临床组织样本中，Sema4D 高水平表达，其表达与胰岛素样生长因子-I（IGF-I）表达相关。体外实验表明，IGF-I 调节 Sema4D 的表达，Sema4D 增加 HNSCC 细胞的增殖、迁移和侵袭。Sema4D 还调节破骨细胞前体细胞中核因子 κβ 配体受体激活剂（RANKL）的表达，从而刺激破骨细胞生成。此外，在 HNSCC 细胞中敲低 Sema4D 抑制肿瘤生长并减少小鼠异种移植模型中破骨细胞的数量。综上所述，HNSCC 中 IGF-I 驱动的 Sema4D 产生促进破骨细胞生成和骨侵袭。
