The acquisition of motility via epithelial-mesenchymal transition (EMT) and osteoclast induction are essential for the invasion and metastasis of oral squamous cell carcinoma (OSCC) to bone. However, the molecule suppressing both EMT and osteoclastogenesis is still unknown. In this study, we found that cellular communication network factor 6 (CCN6) was less produced in a human OSCC cell line, HSC-3 with mesenchymal phenotype, than in HSC-2 cells without it. Notably, CCN6 interacted with bone morphogenetic protein 2 (BMP2) and suppressed the cell migration of HSC-3 cells stimulated by BMP2. Moreover, knockdown of CCN6 in HSC-2 cells led to the promotion of EMT and enhanced the effect of transforming growth factor-β (TGF-β) on the promotion of EMT. Furthermore, CCN6 combined with BMP2 suppressed EMT. These results suggest that CCN6 strongly suppresses EMT in cooperation with BMP2 and TGF-β. Interestingly, CCN6 combined with BMP2 increased the gene expression of receptor activator of nuclear factor-κB ligand (RANKL) in HSC-2 and HSC-3 cells. Additionally, CCN6 interacted with RANKL, and CCN6 combined with RANKL suppressed RANKL-induced osteoclast formation. In metastatic lesions, increasing BMP2 due to the bone destruction led to interference with binding of CCN6 to RANKL, which results in the promotion of bone metastasis of OSCC cells due to continuous osteoclastogenesis. These findings suggest that CCN6 plays dual roles in the suppression of EMT and in the promotion of bone destruction of OSCC in primary and metastatic lesions, respectively, through cooperation with BMP2 and interference with RANKL.

中文翻译：

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细胞通讯网络因子 6 (CCN6) 通过与 BMP2 和 RANKL 结合在口腔癌细胞侵袭和骨转移中发挥双重作用。

通过上皮间质转化（EMT）和破骨细胞诱导获得运动对于口腔鳞状细胞癌（OSCC）向骨的侵袭和转移至关重要。然而，抑制 EMT 和破骨细胞生成的分子仍然未知。在这项研究中，我们发现，与不具有间充质表型的 HSC-2 细胞相比，人 OSCC 细胞系（具有间充质表型的 HSC-3）中产生的细胞通讯网络因子 6 (CCN6) 较少。值得注意的是，CCN6 与骨形态发生蛋白 2 (BMP2) 相互作用，并抑制 BMP2 刺激的 HSC-3 细胞的细胞迁移。此外，HSC-2细胞中CCN6的敲低导致EMT的促进，并增强了转化生长因子-β（TGF-β）促进EMT的作用。此外，CCN6 与 BMP2 联合抑制 EMT。这些结果表明CCN6与BMP2和TGF-β协同作用强烈抑制EMT。有趣的是，CCN6与BMP2联合增加了HSC-2和HSC-3细胞中核因子κB配体受体激活剂（RANKL）的基因表达。此外，CCN6 与 RANKL 相互作用，CCN6 与 RANKL 联合抑制 RANKL 诱导的破骨细胞形成。在转移灶中，骨破坏导致BMP2增加，干扰CCN6与RANKL的结合，从而由于持续的破骨细胞生成而促进OSCC细胞的骨转移。这些发现表明，CCN6 通过与 BMP2 配合和干扰 RANKL，分别在原发性和转移性病变中抑制 EMT 和促进 OSCC 骨破坏中发挥双重作用。