Taipei Cancer Center, Taipei Medical University, Taipei, 110, Taiwan.
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 110, Taiwan.
Cell Death Dis. 2018 Sep 20;9(10):955. doi: 10.1038/s41419-018-1008-9.
Chondrosarcomas are primary malignant bone tumors that have a poor prognosis. WNT1-inducible signaling pathway protein-3 (WISP-3, also termed CCN6) belongs to the CCN family of proteins and is implicated in the regulation of various cellular functions, such as cell proliferation, differentiation, and migration. It is unknown as to whether CCN6 affects human chondrosarcoma metastasis. We show how CCN6 promotes chondrosarcoma cell migration and invasion via matrix metallopeptidase-9 (MMP)-9 expression. These effects were abolished by pretreatment of chondrosarcoma cells with PI3K, Akt, mTOR, and NF-κB inhibitors or short interfering (si)RNAs. Our investigations indicate that CCN6 facilitates metastasis through the PI3K/Akt/mTOR/NF-κB signaling pathway. CCN6 and MMP-9 expression was markedly increased in the highly migratory JJ012(S10) cell line compared with the primordial cell line (JJ012) in both in vitro and in vivo experiments. CCN6 knockdown suppressed MMP-9 production in JJ012(S10) cells and attenuated cell migration and invasion ability. Importantly, CCN6 knockdown profoundly inhibited chondrosarcoma cell metastasis to lung. Our findings reveal an important mechanism underlying CCN6-induced metastasis and they highlight the clinical significance between CCN6 and MMP-9 in regard to human chondrosarcoma. CCN6 appears to be a promising therapeutic target in chondrosarcoma metastasis.
软骨肉瘤是一种预后不良的原发性恶性骨肿瘤。WNT1 诱导信号通路蛋白-3（WISP-3，也称为 CCN6）属于 CCN 蛋白家族，参与调节多种细胞功能，如细胞增殖、分化和迁移。目前尚不清楚 CCN6 是否影响人类软骨肉瘤的转移。我们展示了 CCN6 如何通过基质金属蛋白酶-9（MMP-9）的表达促进软骨肉瘤细胞的迁移和侵袭。这些作用可以通过预先用 PI3K、Akt、mTOR 和 NF-κB 抑制剂或短发夹 RNA（siRNA）处理软骨肉瘤细胞而被消除。我们的研究表明，CCN6 通过 PI3K/Akt/mTOR/NF-κB 信号通路促进转移。在体外和体内实验中，与原始细胞系（JJ012）相比，高度迁移的 JJ012(S10)细胞系中 CCN6 和 MMP-9 的表达明显增加。CCN6 敲低抑制了 JJ012(S10)细胞中 MMP-9 的产生，并减弱了细胞迁移和侵袭能力。重要的是，CCN6 敲低显著抑制了软骨肉瘤细胞向肺的转移。我们的研究结果揭示了 CCN6 诱导转移的重要机制，并强调了 CCN6 和 MMP-9 在人类软骨肉瘤中的临床意义。CCN6 似乎是软骨肉瘤转移的一个有前途的治疗靶点。
