The expression of Wnt-inhibitor DKK1 (Dickkopf 1) is determined by intercellular crosstalk and hypoxia in human malignant gliomas
The expression of Wnt-inhibitor DKK1 (Dickkopf 1) is determined by intercellular crosstalk and hypoxia in human malignant gliomas
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DOI：
10.1007/s00432-014-1642-2
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发表时间：
2014-08-01
影响因子：
3.6
通讯作者：
Schichor, Christian
中科院分区：
文献类型：
--
作者：
Guo, Ke-Tai;Fu, Peng;Schichor, Christian
目的Wnt信号通路调节多种人类细胞的增殖、运动和存活。Dickkopf 1（DKK 1）基因编码分泌的Wnt抑制因子。它在乳腺癌中作为肿瘤抑制基因，在神经胶质瘤细胞中作为促凋亡因子。本研究旨在探讨DKK 1在人脑胶质瘤细胞中的差异表达是否受缺氧等微环境因素的影响，以及DKK 1与骨髓间充质干细胞（bmMSCs）之间的细胞间串扰的调控。采用实时荧光定量PCR和酶联免疫吸附试验检测常氧/低氧环境及共培养条件下细胞系中DKK 1的表达。结果胶质瘤源性细胞U87-MG中DKK 1的表达明显低于bmMSCs。与常氧环境相比，缺氧导致DKK 1在bmMSCs和U87-MG中过表达，而U87-MG与bmMSCs共培养诱导DKK 1在两种细胞系中的表达。外源性重组DKK 1对所有细胞系的迁移均有抑制作用，但对bmMSCs和胶质瘤细胞系的增殖无明显影响。结论在本研究中，我们首次证明了DKK 1在人恶性胶质瘤细胞系中的表达具有缺氧依赖性。细胞内串扰或缺氧刺激诱导DKK 1揭示了神经胶质肿瘤细胞对环境变化的强烈适应。
Objective Wnt signalling pathways regulate proliferation, motility and survival in a variety of human cell types. Dickkopf 1 (DKK1) gene codes for a secreted Wnt inhibitory factor. It functions as tumour suppressor gene in breast cancer and as a pro-apoptotic factor in glioma cells. In this study, we aimed to demonstrate whether the different expression of DKK1 in human glioma-derived cells is dependent on microenvironmental factors like hypoxia and regulated by the intercellular crosstalk with bone-marrow-derived mesenchymal stem cells (bmMSCs).Methods Glioma cell line U87-MG, three cell lines from human glioblastoma grade IV (glioma-derived mesenchymal stem cells) and three bmMSCs were selected for the experiment. The expression of DKK1 in cell lines under normoxic/hypoxic environment or co-culture condition was measured using real-time PCR and enzyme-linked immunoadsorbent assay. The effect of DKK1 on cell migration and proliferation was evaluated by in vitro wound healing assays and sulphorhodamine assays, respectively.Results Glioma-derived cells U87-MG displayed lower DKK1 expression compared with bmMSCs. Hypoxia led to an overexpression of DKK1 in bmMSCs and U87-MG when compared to normoxic environment, whereas co-culture of U87-MG with bmMSCs induced the expression of DKK1 in both cell lines. Exogenous recombinant DKK1 inhibited cell migration on all cell lines, but did not have a significant effect on cell proliferation of bmMSCs and glioma cell lines.Conclusion In this study, we showed for the first time that the expression of DKK1 was hypoxia dependent in human malignant glioma cell lines. The induction of DKK1 by intracellular crosstalk or hypoxia stimuli sheds light on the intense adaption of glial tumour cells to environmental alterations.