Department of Medical Genetics, Yeditepe University Medical School, 34755, Istanbul, Turkey; Department of Genetics and Bioengineering, Yeditepe University, 34755, Istanbul, Turkey.
Department of Neurosurgery, Yeditepe University Medical School, Yeditepe University, 34755, Istanbul, Turkey.
Exp Cell Res. 2019 Jul 1;380(1):9-19. doi: 10.1016/j.yexcr.2019.03.039. Epub 2019 Apr 2.
Chordoma is a rare, slow-growing tumor thought to arise from remnants of embryonic notochord associated with an aggressive outcome. Cancer stem-like cells (CSCs) are related to tumorigenesis, recurrence, and resistance in cancers. Therefore, chordoma CSCs are possible targets for chordoma treatment. In this study, dysregulated miRNAs were determined in chordoma CSCs and identified their role in chordoma. Dysregulated miRNAs were determined via miRNA microarray and validated through qPCR. miRNAs were transiently transfected to the chordoma cell lines and their roles in proliferation, apoptosis, migration and invasion capacities and stem-like properties were identified. Finally, a relationship between clinicopathological features and dysregulated miRNAs has been evaluated among 21 chordoma patients. CD133CD15 cells exhibited CSC phenotype with increased CSC- and Epithelial-Mesenchymal Transition (EMT)-related gene expression, invasion, migration, tumorosphere- and colony-forming abilities. In addition, WNT5A, TGF-α, BTG2 and MYCBP genes involved in CSC-related pathways, were targets of miR-140-3p, miR-148a-3p, miR-210-5p and miR-574-5p, respectively. Transfection of CSC-related miRNAs also increased migration and invasion along with stem cell phenotype. Finally, we determined that miR-140-3p and miR-148a-3p expressions correlated with Ki67 while miR-140-3p and TGF-α expressions were correlated with p53. Moreover, MYCBP expression was positively correlated with tumor volume, and metastasis was associated with the expression of miR-210-5p and TGF-α in our patient cohort. Through these findings, we conclude that chordoma CSCs have distinctive miRNA profile, which can regulate stem-like properties of chordoma CSCs.
软骨肉瘤是一种罕见的、生长缓慢的肿瘤，被认为起源于与侵袭性结果相关的胚胎脊索残余物。癌症干细胞样细胞（CSC）与癌症的发生、复发和耐药性有关。因此，软骨肉瘤 CSC 可能是软骨肉瘤治疗的靶点。在这项研究中，确定了软骨肉瘤 CSC 中的失调 miRNA，并鉴定了它们在软骨肉瘤中的作用。通过 miRNA 微阵列确定失调 miRNA，并通过 qPCR 进行验证。将 miRNA 瞬时转染到软骨肉瘤细胞系中，鉴定它们在增殖、凋亡、迁移和侵袭能力以及干细胞样特性中的作用。最后，在 21 名软骨肉瘤患者中评估了临床病理特征与失调 miRNA 之间的关系。CD133CD15 细胞表现出 CSC 表型，具有增加的 CSC 和上皮-间充质转化（EMT）相关基因表达、侵袭、迁移、肿瘤球和集落形成能力。此外，WNT5A、TGF-α、BTG2 和 MYCBP 基因参与 CSC 相关途径，分别是 miR-140-3p、miR-148a-3p、miR-210-5p 和 miR-574-5p 的靶标。CSC 相关 miRNA 的转染也增加了迁移和侵袭以及干细胞表型。最后，我们确定 miR-140-3p 和 miR-148a-3p 的表达与 Ki67 相关，而 miR-140-3p 和 TGF-α 的表达与 p53 相关。此外，MYCBP 表达与肿瘤体积呈正相关，而在我们的患者队列中，转移与 miR-210-5p 和 TGF-α 的表达相关。通过这些发现，我们得出结论，软骨肉瘤 CSC 具有独特的 miRNA 谱，可以调节软骨肉瘤 CSC 的干细胞样特性。
