The inhibition of RANKL/RANK signaling by osteoprotegerin suppresses bone invasion by oral squamous cell carcinoma cells
The inhibition of RANKL/RANK signaling by osteoprotegerin suppresses bone invasion by oral squamous cell carcinoma cells
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DOI：
10.1093/carcin/bgr198
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发表时间：
2011-11-01
期刊：
影响因子：
4.7
通讯作者：
Jimi, Eijiro
中科院分区：
文献类型：
--
作者：
Shin, Masashi;Matsuo, Kou;Jimi, Eijiro
口腔鳞状细胞癌是一种常见的侵犯上颌骨和下颌骨的恶性肿瘤。然而，OSCC骨侵袭的分子机制尚不清楚。近年来研究发现，核因子κ B受体激活因子（RANK）不仅在破骨细胞前体细胞中表达，而且在肿瘤细胞中也有表达。因此，我们研究了RANK配体（RANKL）/RANK信号转导是否在体内和体外调节OSCC细胞的骨侵袭。我们首先将人口腔鳞状细胞癌B88细胞注射到裸鼠的咬肌区。用RANKL的诱饵受体骨保护素（OPG）处理小鼠3周。OPG可降低B88细胞的骨侵袭能力，减少破骨细胞数量，增加B88细胞凋亡。然而，OPG在体外对B88细胞的凋亡和增殖没有影响，这表明OPG对B88细胞凋亡的影响在骨环境中是有限的。RANK在患者的B88细胞和OSCC细胞中表达。RANKL诱导B88细胞中NF-κ B活化和细胞外信号调节激酶磷酸化，并在配备明胶涂层过滤器的改良趋化室中增强B88细胞迁移。OPG抑制RANKL诱导的NF-κ B活化、细胞外信号调节激酶磷酸化和细胞迁移。我们的数据清楚地表明，RANKL/RANK抑制通过抑制破骨细胞生成和癌细胞迁移以及通过体内间接抗癌作用诱导癌细胞凋亡来抑制骨侵袭。
Oral squamous cell carcinomas (OSCCs) are malignant tumors that frequently invade the maxilla and mandibular bone. However, the molecular mechanisms underlying bone invasion by OSCC are unclear. Recent studies showed that receptor activator of nuclear factor kappa B (RANK) was expressed not only in osteoclast precursors but also in tumor cells. Therefore, we examined whether RANK ligand (RANKL)/RANK signaling regulates bone invasion by OSCC cells in vivo and in vitro. We first injected human OSCC B88 cells into the masseter region of nude mice. Mice were treated for 3 weeks with osteoprotegerin (OPG), the decoy receptor for RANKL. Treatment with OPG decreased bone invasion by B88 cells, reduced the number of osteoclasts and increased B88 cell apoptosis. However, OPG did not affect apoptosis and proliferation in B88 cells in vitro, suggesting that the effects of OPG on apoptosis in B88 cells are restricted in a bone environment. RANK was expressed in the B88 cells and in OSCC cells from patients. RANKL induced NF-kappa B activation and extracellular signal-regulated kinase phosphorylation in B88 cells and enhanced B88 cell migration in a modified chemotaxis chamber equipped with a gelatin-coated filter. OPG inhibited RANKL-induced NF-kappa B activation, extracellular signal-regulated kinase phosphorylation and cell migration. Our data clearly indicate that RANKL/RANK inhibition suppresses bone invasion by inhibiting osteoclastogenesis and cancer cell migration and by inducing apoptosis of cancer cells via indirect anticancer action in vivo.