Cerebral Tumour Research Group, Hormones and Cancer, Kolling Institute of Medical Research, NSW, Australia.
Eur J Cancer. 2011 Apr;47(6):953-63. doi: 10.1016/j.ejca.2010.11.026. Epub 2010 Dec 31.
Glioblastoma (GBM) represents a formidable clinical challenge for both patients and treating physicians. Due to better local treatments and prolonged patient survival, remote recurrences are increasingly observed, underpinning the importance of targeting tumour migration and attachment. Aberrant expression of microRNA (miRNA) is commonly associated with cancer and loss of miR-124a has previously been implicated to function as a tumour suppressor. The assessment of miR-124a in clinical specimens has been limited and a potential role in migration and invasion has been unexplored until now. We measured the expression levels of mature miR-124a in a retrospective series of 119 cases of histologically confirmed GBM and found its expression was markedly lower in over 80% of the GBM clinical specimens compared to normal brain tissue. The level of reduction in the clinical cohort varied significantly and patients with lower than the average miR-124a expression levels displayed shorter survival times. Endogenous miR-124a expression and the protein expression of three of its targets; IQ motif containing GTPase activating protein 1 (IQGAP1), laminin γ1 (LAMC1) and integrin β1 (ITGB1) were significantly reciprocally associated in the majority of the clinical cases. We confirmed this association in our in vitro model. Functionally, the ectopic expression of mature miR-124a in a GBM cell line resulted in significant inhibition of migration and invasion, demonstrating a role for miR-124a in promoting tumour invasiveness. Our results suggest that miR-124a may play a role in GBM migration, and that targeted delivery of miR-124a may be a novel inhibitor of GBM invasion.
胶质母细胞瘤（GBM）对患者和治疗医生来说都是一个严峻的临床挑战。由于局部治疗效果的改善和患者生存时间的延长，越来越多的患者出现远处复发，这凸显了靶向肿瘤迁移和黏附的重要性。miRNA（miRNA）的异常表达通常与癌症有关，miR-124a 的缺失先前被认为具有肿瘤抑制作用。miR-124a 在临床标本中的评估受到限制，其在迁移和侵袭中的潜在作用至今尚未得到探索。我们在 119 例经组织学证实的 GBM 回顾性系列中测量了成熟 miR-124a 的表达水平，发现其在超过 80%的 GBM 临床标本中的表达明显低于正常脑组织。在临床队列中，减少的水平差异显著，miR-124a 表达水平低于平均值的患者存活时间较短。在大多数临床病例中，内源性 miR-124a 表达与其三个靶标（IQ 基序包含 GTPase 激活蛋白 1（IQGAP1）、层粘连蛋白γ1（LAMC1）和整合素β1（ITGB1）的蛋白表达水平呈显著的相互关联。我们在体外模型中证实了这种关联。功能上，在 GBM 细胞系中外源性表达成熟 miR-124a 导致迁移和侵袭显著抑制，表明 miR-124a 在促进肿瘤侵袭性方面发挥作用。我们的研究结果表明，miR-124a 可能在 GBM 迁移中发挥作用，靶向递送 miR-124a 可能是 GBM 侵袭的一种新型抑制剂。
