Ror1 is expressed inducibly by Notch and hypoxia signaling and regulates stem cell-like property of glioblastoma cells.
Ror1 is expressed inducibly by Notch and hypoxia signaling and regulates stem cell-like property of glioblastoma cells.
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Ror1通过调节细胞增殖和迁移在癌症进展中起着至关重要的作用。Ror1在各种类型的癌细胞和癌症干细胞样细胞中大量表达。然而，在这些细胞中调节Ror1表达的分子机制在很大程度上仍然未知。Ror1及其推测的配体Wnt5a在恶性胶质瘤中，尤其是在胶质母细胞瘤中高表达，且Ror1的表达程度与胶质瘤患者预后较差呈正相关。我们发现，在球状培养条件下，Ror1在胶质母细胞瘤细胞中的表达可以上调，而不是贴壁培养条件。Notch和缺氧信号通路在球状胶质母细胞瘤干细胞样细胞（GSCs）中被激活，并且Ror1在胶质母细胞瘤细胞中的表达确实通过抑制Notch或缺氧信号通路而受到抑制。同时，在胶质母细胞瘤细胞中强制表达Notch胞内结构域（NICD）或缺氧培养均可导致细胞中Ror1的表达增强。一致地，我们发现在球形培养条件下，NICD和缺氧诱导因子1 α在GSCs中更有效地结合到Ror1基因的上游区域。此外，我们提供的证据表明，Wnt5a与Ror1的结合，在GSCs中被Notch和缺氧信号通路上调，可能促进它们的球形形成能力。总的来说，这些发现首次表明Notch和缺氧信号通路可以通过转录激活胶质母细胞瘤细胞中的Ror1引发Wnt5a-Ror1轴，从而促进其干细胞样特性。在这项研究中，我们首次发现在胶质母细胞瘤细胞中，Ror1的表达被Notch和缺氧信号通路上调，尤其是具有干细胞样特征的细胞。我们目前的研究结果表明，Notch和缺氧信号通路激活的Wnt5a‐Ror1轴可能在调节胶质母细胞瘤细胞的干性中发挥重要作用。
Ror1 plays a crucial role in cancer progression by regulating cell proliferation and migration. Ror1 is expressed abundantly in various types of cancer cells and cancer stem‐like cells. However, the molecular mechanisms regulating expression of Ror1 in these cells remain largely unknown. Ror1 and its putative ligand Wnt5a are expressed highly in malignant gliomas, especially in glioblastomas, and the extents of Ror1 expression are correlated positively with poorer prognosis in patients with gliomas. We show that Ror1 expression can be upregulated in glioblastoma cells under spheroid culture, but not adherent culture conditions. Notch and hypoxia signaling pathways have been shown to be activated in spheroid‐forming glioblastoma stem‐like cells (GSCs), and Ror1 expression in glioblastoma cells is indeed suppressed by inhibiting either Notch or hypoxia signaling. Meanwhile, either forced expression of the Notch intracellular domain (NICD) in or hypoxic culture of glioblastoma cells result in enhanced expression of Ror1 in the cells. Consistently, we show that both NICD and hypoxia‐inducible factor 1 alpha bind to upstream regions within the Ror1 gene more efficiently in GSCs under spheroid culture conditions. Furthermore, we provide evidence indicating that binding of Wnt5a to Ror1, upregulated by Notch and hypoxia signaling pathways in GSCs, might promote their spheroid‐forming ability. Collectively, these findings indicate for the first time that Notch and hypoxia signaling pathways can elicit a Wnt5a–Ror1 axis through transcriptional activation of Ror1 in glioblastoma cells, thereby promoting their stem cell‐like property. In this study, we show for the first time that expression of Ror1 is up‐regulated by Notch and hypoxia signaling pathways in glioblastoma cells, especially with stem cell‐like characteristics. Our present findings indicate that Wnt5a‐Ror1 axis activated by Notch and hypoxia signaling pathways might play important roles in regulating the stemness of glioblastoma cells.
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18.4
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