Blocking signaling at the level of GLI regulates downstream gene expression and inhibits proliferation of canine osteosarcoma cells.
Blocking signaling at the level of GLI regulates downstream gene expression and inhibits proliferation of canine osteosarcoma cells.
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DOI：
10.1371/journal.pone.0096593
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Rebhun RB
中科院分区：
文献类型：
--
作者：
Shahi MH;Holt R;Rebhun RB
刺猬- gli信号通路在多种人类恶性肿瘤中都很活跃，并且已知对人类骨肉瘤细胞的生长和存活有贡献。在本研究中，我们检测了GLI转录因子在多种犬骨肉瘤细胞系中的表达和调控，并分析了GLI特异性抑制剂GANT61对GLI的抑制作用。real-time PCR结果显示，与正常犬成骨细胞相比，GLI1和GLI2在三种细胞系中有两种呈高表达，并与下游靶基因ptch1和PAX6的表达相关。用GANT61治疗犬骨肉瘤细胞导致GLI1、GLI2、PTCH1和PAX6的表达降低。此外，GANT61抑制了所有三种犬骨肉瘤细胞系的增殖和集落形成。GLI信号活性在犬骨肉瘤细胞中存在且活跃的研究结果表明，犬自发产生的骨肉瘤可能为GLI抑制剂的临床前测试提供良好的模型。
The Hedgehog-GLI signaling pathway is active in a variety of human malignancies and is known to contribute to the growth and survival of human osteosarcoma cells. In this study, we examined the expression and regulation of GLI transcription factors in multiple canine osteosarcoma cell lines and analyzed the effects of inhibiting GLI with GANT61, a GLI-specific inhibitor. Compared with normal canine osteoblasts, real-time PCR showed that GLI1 and GLI2 were highly expressed in two out of three cell lines and correlated with downstream target gene expression of PTCH1and PAX6. Treatment of canine osteosarcoma cells with GANT61 resulted in decreased expression of GLI1, GLI2, PTCH1, and PAX6. Furthermore, GANT61 inhibited proliferation and colony formation in all three canine osteosarcoma cell lines. The finding that GLI signaling activity is present and active in canine osteosarcoma cells suggests that spontaneously arising osteosarcoma in dogs might serve as a good model for future preclinical testing of GLI inhibitors.
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