Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan.
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
J Neurochem. 2018 Aug;146(3):269-288. doi: 10.1111/jnc.14459.
Glioblastoma multiforme is the most common brain tumor in adults. Because of its highly invasive nature, it is not easy to treat, resulting in high mortality rates. Stromal interacting molecule 1 (Stim1) plays important roles in regulating store-operated Ca entry, and controls invasion by cancer cells. However, the mechanisms and functions of Stim1 in glioma progression are still unclear. In this study, we investigated the effects of targeting Stim1 expression on glioma cell invasion. By analyzing profiles of glioblastoma multiforme patients from RNA-sequencing data in The Cancer Genome Atlas, higher expression levels of STIM1 were correlated with the poor survival. Furthermore, signaling pathways associated with tumor malignancy, including the epithelial-to-mesenchymal transition (EMT), were activated in patients with high STIM1 expression according to gene set enrichment analyses. Higher Stim1 levels were found in glioma cells compared to human astrocytes, and these higher levels enhanced glioma cell invasion. Xanthohumol (XN), a prenylated flavonoid extracted from the hop plant Humulus lupulus L. (Cannabaceae), significantly reduced cell invasion through inhibiting Stim1 expression. From an micro(mi)RNA array analysis, miR-4725-3p was up-regulated by XN treatment. Over-expression of miR-4725-3p inhibited glioma cell invasion via directly targeting the 3'-untranslated region of STIM1. The extracellular signal-regulated kinase/c-Fos pathway was also validated to participate in XN-up-regulated miR-4725-3p expression according to promoter and chromatin immunoprecipitation assays. These results emphasize that miR-4725-3p-inhibited STIM1 signaling is involved in XN-attenuated glioma cell invasion. These findings may provide insights into novel therapeutic strategies for future glioblastoma therapy and drug development. Open Data: Materials are available on https://cos.io/our-services/open-science-badges/ https://osf.io/93n6m/.
胶质母细胞瘤是成人中最常见的脑肿瘤。由于其高度侵袭性，治疗起来并不容易，导致死亡率很高。基质相互作用分子 1（Stim1）在调节储存操作的 Ca 内流中发挥重要作用，并控制癌细胞的侵袭。然而，Stim1 在神经胶质瘤进展中的机制和功能仍不清楚。在这项研究中，我们研究了靶向 Stim1 表达对神经胶质瘤细胞侵袭的影响。通过分析来自癌症基因组图谱中 RNA 测序数据的胶质母细胞瘤患者的图谱，我们发现 Stim1 的高表达与患者的不良预后相关。此外，根据基因集富集分析，与肿瘤恶性相关的信号通路，包括上皮间质转化（EMT），在 Stim1 高表达的患者中被激活。与人类星形胶质细胞相比，神经胶质瘤细胞中发现的 Stim1 水平更高，并且这些更高水平增强了神经胶质瘤细胞的侵袭性。黄腐醇（XN），一种从啤酒花植物啤酒花（大麻科）中提取的类异戊二烯化黄酮，通过抑制 Stim1 表达显著降低细胞侵袭。通过 micro(mi)RNA 阵列分析，XN 处理上调了 miR-4725-3p。通过直接靶向 Stim1 的 3'-非翻译区，过表达 miR-4725-3p 抑制神经胶质瘤细胞侵袭。根据启动子和染色质免疫沉淀测定，细胞外信号调节激酶/c-Fos 通路也被验证参与了 XN 上调的 miR-4725-3p 表达。这些结果强调了 miR-4725-3p 抑制的 Stim1 信号参与了 XN 减弱神经胶质瘤细胞侵袭的过程。这些发现可能为未来的神经胶质瘤治疗和药物开发提供新的治疗策略的思路。开放数据：材料可在 https://cos.io/our-services/open-science-badges/ https://osf.io/93n6m/ 上获取。
