Journal of Orthopaedic Translation ( IF 6.6 ) Pub Date : 2022-03-11 , DOI: 10.1016/j.jot.2021.12.001 Feng-Wei Zhang 1, 2 , Li-Yang Peng 1, 2 , Chuan-Jian Shi 3, 4 , Jian-Chi Li 5 , Feng-Xiang Pang 1, 2 , Wei-Ming Fu 3, 4 , Xiao-Hua Pan 6 , Jin-Fang Zhang 1, 2
Background
Osteosarcoma (OS) is a common type of malignant bone tumor in adolescents with high risk of metastasis. However, the clinical management still remains unsatisfactory. Traditional Chinese medicine (TCM) has been widely considered as an alternative treatment, and their extracts have proved to possess great potential for drug discovery. Baicalein (BA), the active pharmaceutical ingredient of rhizoma coptidis, was proved to have anti-tumor properties in OS, but the mechanism remains poorly understood.
Methods
The potential anti-cancer effects on cell growth, cell cycle, apoptosis and migration were examined in OS cells. Moreover, the lncRNA-Neighboring Enhancer of FOXA2 (lncRNA-NEF) and Wnt/β-catenin signaling were detected by qPCR and Western blotting assays. The in vivo effect of GA on tumor growth was investigated using a xenograft mice model.
Results
In the present study, BA was found to significantly suppress tumor growth in vitro and in vivo. And it was also found to inhibit the invasion and metastasis as well. As for the mechanism investigation, lncRNA-NEF was obviously upregulated by BA in OS cells, and thus induced the inactivation of Wnt/β-catenin signaling. Moreover, lncRNA-NEF knockdown partially reversed the BA-induced anti-cancer activities; and successfully compensated the suppressive effect on Wnt/β-catenin signaling. We therefore suggested that BA induced the inactivation of Wnt/β-catenin signaling through promoting lncRNA-NEF expression.
Conclusions
In conclude, our results demonstrated that BA suppressed tumor growth and metastasis in vitro and in vivo through an lncRNA-NEF driven Wnt/β-catenin regulatory axis, in which lncRNA-NEF was upregulated by BA, and thus induced the inactivation of Wnt/β-catenin signaling.
The Translational potential of this article
The findings derived from this study validates the anti-cancer activity of BA in OS and provides a novel underlying mechanism, which suggest that BA may be a potential candidate to develop the effective drug for OS patients.
中文翻译:
黄芩素通过 lncRNA-NEF 驱动的 Wnt/β-catenin 信号调节轴介导骨肉瘤的抗肿瘤活性
背景
骨肉瘤(OS)是青少年常见的恶性骨肿瘤,具有高转移风险。然而,临床管理仍然不尽如人意。中药(TCM)已被广泛认为是一种替代疗法,其提取物已被证明具有巨大的药物发现潜力。黄连的活性药物成分黄芩素 (BA)已被证明在 OS 中具有抗肿瘤特性,但其机制仍知之甚少。
方法
在 OS 细胞中检测了对细胞生长、细胞周期、细胞凋亡和迁移的潜在抗癌作用。此外,通过 qPCR 和蛋白质印迹分析检测了 FOXA2 的 lncRNA-Neighboring Enhancer (lncRNA-NEF) 和 Wnt/β-catenin 信号传导。使用异种移植小鼠模型研究了 GA 对肿瘤生长的体内影响。
结果
在本研究中,发现 BA在体外和体内显着抑制肿瘤生长。并且还发现它还可以抑制侵袭和转移。至于机制研究,lncRNA-NEF在OS细胞中被BA明显上调,从而诱导Wnt/β-catenin信号通路失活。此外,lncRNA-NEF 敲低部分逆转了 BA 诱导的抗癌活性;并成功补偿了对 Wnt/β-catenin 信号传导的抑制作用。因此,我们建议 BA 通过促进 lncRNA-NEF 表达来诱导 Wnt/β-catenin 信号的失活。
结论
总之,我们的研究结果表明,BA通过 lncRNA-NEF 驱动的 Wnt/β-catenin 调节轴在体外和体内抑制肿瘤生长和转移,其中 lncRNA-NEF 被 BA 上调,从而诱导 Wnt/ β-连环蛋白信号。
本文的转化潜力
本研究的结果验证了 BA 在 OS 中的抗癌活性,并提供了一种新的潜在机制,这表明 BA 可能是开发 OS 患者有效药物的潜在候选者。