Diallyl trisulfide inhibits proliferation, invasion and angiogenesis of osteosarcoma cells by switching on suppressor microRNAs and inactivating of Notch-1 signaling
Diallyl trisulfide inhibits proliferation, invasion and angiogenesis of osteosarcoma cells by switching on suppressor microRNAs and inactivating of Notch-1 signaling
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DOI：
10.1093/carcin/bgt065
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发表时间：
2013-07-01
期刊：
影响因子：
4.7
通讯作者：
Li, Jianmin
中科院分区：
文献类型：
--
作者：
Li, Yonggang;Zhang, Jingru;Li, Jianmin
Notch信号通路在包括骨肉瘤在内的人类癌症中发挥着关键作用，这表明针对Notch的特异性药物的发现对于骨肉瘤极其有价值。我们之前的研究表明，二烯丙基三硫化物（DATS）通过在体外触发细胞周期停滞和细胞凋亡来抑制骨肉瘤细胞的增殖。然而，其根本机制仍不清楚。在这项研究中，我们发现 DATS 抑制骨肉瘤细胞的细胞存活、伤口愈合能力、侵袭和血管生成。这些效应与 Notch-1 及其下游基因（如血管内皮生长因子和基质金属蛋白酶）的表达降低以及一组肿瘤抑制性 microRNA (miRNA) 的表达增加有关，包括通常在骨肉瘤中丢失的 miR-34a、miR-143、miR-145 和 miR-200b/c。我们还发现，通过转染重新表达miR-34a和miR-200b会导致Notch-1表达减少，从而抑制骨肉瘤细胞增殖、侵袭和血管生成。这些结果清楚地表明，DATS 通过一种针对 NotchmiRNA 调节回路的新机制抑制骨肉瘤的生长和侵袭性。我们的数据提供了第一个证据，表明 DATS 下调 Notch-1 和 miRNA 重新表达可能是治疗骨肉瘤的有效方法。
Notch signaling pathway plays critical roles in human cancers, including osteosarcoma, suggesting that the discovery of specific agents targeting Notch would be extremely valuable for osteosarcoma. Our previous studies have shown that diallyl trisulfide (DATS) inhibits proliferation of osteosarcoma cells by triggering cell cycle arrest and apoptosis in vitro. However, the underlying mechanism is still unclear. In this study, we found that DATS suppressed cell survival, wound-healing capacity, invasion and angiogenesis in osteosarcoma cells. These effects were associated with decreased expression of Notch-1 and its downstream genes, such as vascular endothelial growth factor and matrix metalloproteinases, as well as increased expression of a panel of tumor-suppressive microRNAs (miRNAs), including miR-34a, miR-143, miR-145 and miR-200b/c that are typically lost in osteosarcoma. We also found that reexpression of miR-34a and miR-200b by transfection led to reduced expression of Notch-1, resulting in the inhibition of osteosarcoma cell proliferation, invasion and angiogenesis. These results clearly suggest that DATS inhibited osteosarcoma growth and aggressiveness via a novel mechanism targeting a NotchmiRNA regulatory circuit. Our data provide the first evidence that the downregulation of Notch-1 and reexpression of miRNAs by DATS may be an effective approach for the treatment of osteosarcoma.