Abstract

Hypoxia is a typical feature of solid tumors and is closely associated with tumor progression. Sauchinone, a biologically diastereomeric lignan, is isolated from the root of Saururus chinensis and has been widely used for the treatment of various diseases. Recently, sauchinone has been reported to play an anti-cancer role in cancer development under normoxia or hypoxia. However, the specific effects of sauchinone on osteosarcoma (OS) remain unclear. The aim of the present study was to investigate the role of sauchinone in OS progression under hypoxic conditions. The human OS cell lines U2OS and MG-63 were exposed to hypoxia followed by treatment with sauchinone. Cell viability was assessed by the CCK-8 assay. Cell migration and invasion were detected by transwell assays. The expression levels of VEGF, HIF-1α, E-cadherin and N-cadherin were examined by the western blot analysis. Our study showed that OS cell migration and invasion were significantly enhanced by hypoxia. Besides, hypoxic conditions resulted in a remarkable change in the expression of EMT markers. All these effects induced by hypoxia were abrogated by sauchinone treatment. Moreover, sauchinone inhibited hypoxia-induced activation of the sonic hedgehog (Shh) pathway. Additionally, the Shh agonist reversed the inhibitory effect of sauchinone on hypoxia-induced invasion and EMT of OS cells. In conclusion, these findings demonstrated that sauchinone inhibits hypoxia-induced invasion and EMT in OS cells via inactivation of the Shh pathway. We provided a novel insight for understanding the mechanisms underlying the anti-cancer effect of sauchinone and suggested sauchinone as a promising agent for OS treatment.

摘要

缺氧是实体瘤的典型特征，与肿瘤进展密切相关。Sauchinone 是一种生物非对映体木脂素，从三白草的根中分离得到，已广泛用于治疗各种疾病。最近，有报道称，在常氧或缺氧条件下，sauchinone 在癌症发展中发挥抗癌作用。然而，sauchinone 对骨肉瘤 (OS) 的具体作用仍不清楚。本研究的目的是调查在缺氧条件下，sauchinone 在 OS 进展中的作用。人类 OS 细胞系 U2OS 和 MG-63 暴露于缺氧状态，然后用沙丁酮处理。通过CCK-8测定评估细胞活力。通过 transwell 测定法检测细胞迁移和侵袭。VEGF、HIF-1α、通过蛋白质印迹分析检查E-钙粘蛋白和N-钙粘蛋白。我们的研究表明，缺氧显着增强了 OS 细胞的迁移和侵袭。此外，缺氧条件导致EMT标志物表达发生显着变化。所有这些由缺氧引起的影响都被沙丁酮处理消除了。此外，sauchinone 抑制缺氧诱导的声波刺猬 (Shh) 通路的激活。此外，Shh 激动剂逆转了 sauchinone 对缺氧诱导的 OS 细胞侵袭和 EMT 的抑制作用。总之，这些发现表明，sauchinone 抑制 OS 细胞中缺氧诱导的侵袭和 EMT 缺氧条件导致 EMT 标志物表达发生显着变化。所有这些由缺氧引起的影响都被沙丁酮处理消除了。此外，sauchinone 抑制缺氧诱导的声波刺猬 (Shh) 通路的激活。此外，Shh 激动剂逆转了 sauchinone 对缺氧诱导的 OS 细胞侵袭和 EMT 的抑制作用。总之，这些发现表明，sauchinone 抑制 OS 细胞中缺氧诱导的侵袭和 EMT 缺氧条件导致 EMT 标志物表达发生显着变化。所有这些由缺氧引起的影响都被沙丁酮处理消除了。此外，sauchinone 抑制缺氧诱导的声波刺猬 (Shh) 通路的激活。此外，Shh 激动剂逆转了 sauchinone 对缺氧诱导的 OS 细胞侵袭和 EMT 的抑制作用。总之，这些发现表明，sauchinone 抑制 OS 细胞中缺氧诱导的侵袭和 EMT通过Shh途径的失活。我们提供了一种新的见解，以了解紫苏酮的抗癌作用机制，并建议紫苏酮作为一种有前途的 OS 治疗剂。