Aftab Qurratulain, Sin Wun-Chey, Naus Christian C
Department of Cellular & Physiological Sciences, Life Sciences Institute, The University of British Columbia, Vancouver, BC.
Oncotarget. 2015 May 10;6(13):11447-64. doi: 10.18632/oncotarget.3407.
Glioblastoma Multiforme (GBM), an aggressive form of adult brain tumor, is difficult to treat due to its invasive nature. One of the molecular changes observed in GBM is a decrease in the expression of the gap junction protein Connexin43 (Cx43); however, how a reduction in Cx43 expression contributes to glioma malignancy is still unclear. In this study we examine whether a decrease in Cx43 protein expression has a role in enhanced cell migration, a key feature associated with increased tumorigenicity. We used a 3D spheroid migration model that mimics the in vivo architecture of tumor cells to quantify migration changes. We found that down-regulation of Cx43 expression in the U118 human glioma cell line increased migration by reducing cell-ECM adhesion, and changed the migration pattern from collective to single cell. In addition gap junction intercellular communication (GJIC) played a more prominent role in mediating migration than the cytoplasmic interactions of the C-terminal tail. Live imaging revealed that reducing Cx43 expression enhanced relative migration by increasing the cell speed and affecting the direction of migration. Taken together our findings reveal an unexplored role of GJIC in facilitating collective migration.
多形性胶质母细胞瘤（GBM）是一种侵袭性很强的成人脑肿瘤，因其具有浸润性而难以治疗。在GBM中观察到的分子变化之一是缝隙连接蛋白连接蛋白43（Cx43）的表达降低；然而，Cx43表达的降低如何导致胶质瘤恶性程度增加仍不清楚。在本研究中，我们研究了Cx43蛋白表达的降低是否在增强细胞迁移中起作用，细胞迁移是与肿瘤发生增加相关的一个关键特征。我们使用了一种模拟肿瘤细胞体内结构的三维球体迁移模型来量化迁移变化。我们发现，U118人胶质瘤细胞系中Cx43表达的下调通过减少细胞与细胞外基质的粘附而增加了迁移，并将迁移模式从集体迁移转变为单细胞迁移。此外，缝隙连接细胞间通讯（GJIC）在介导迁移中比C末端尾巴的细胞质相互作用发挥了更突出的作用。实时成像显示，降低Cx43表达通过提高细胞速度和影响迁移方向增强了相对迁移。综上所述，我们的研究结果揭示了GJIC在促进集体迁移中尚未被探索的作用。
