Zhai Yongqing, Liu Min, Zheng Yanping
Department of Orthopedics, Qilu Hospital of Shandong University Jinan, Shandong Province, China.
Department of Orthopedics, Linyi People's Hospital Linyi, Shandong Province, China.
Int J Clin Exp Pathol. 2017 Nov 1;10(11):10989-10997. eCollection 2017.
Cancer cells have developed anoikis resistance and thereby survive after detachment from their primary site and while traveling through the circulation. However, the mechanisms underlying resistance to anoikis in osteosarcoma (OS) remain largely unknown. MicroRNAs (miRNA) have been reported to contribute to malignant phenotypes of cancer cells. To investigate the roles of miRNAs in anoikis resistance of OS cells, the implications of 9 well-characterized miRNAs that dysregulated in OS on cell anoikis were screened. As a result, miR-451 was identified as a crucial factor involved in anoikis resistance and anchorage-independent growth of OS cell. MiR-451 was down-regulated in OS cells, re-expression of miR-451 significantly promoted cell anoikis of three OS cell lines and inhibition of miR-451 protected HOS cells from anoikis under anoikis condition. Subsequently, bioinformatics prediction and luciferase reporter assay indicated that Rab14 was a direct target of miR-451, and Rab14 could be down-regulated by miR-451 at both mRNA and protein levels. Genetic silencing of Rab14 recapitulated the role of miR-451 on anoikis resistance and restoration of Rab14 largely abrogated the tumor suppressor function of miR-451. Finally, overexpression of miR-451 remarkably suppressed the lung metastasis of OS cells. Collectively, our findings suggest that the miR-451/Rab14 axis might serve as a novel mechanism of resistance to anoikis in OS.
癌细胞已产生失巢凋亡抗性，从而在从原发部位脱离并在循环系统中游走时存活下来。然而，骨肉瘤（OS）中抗失巢凋亡的潜在机制仍 largely 未知。据报道，微小核糖核酸（miRNA）有助于癌细胞的恶性表型。为了研究 miRNA 在 OS 细胞抗失巢凋亡中的作用，筛选了 9 种在 OS 中失调的特征明确的 miRNA 对细胞失巢凋亡的影响。结果，miR-451 被确定为参与 OS 细胞抗失巢凋亡和非锚定依赖性生长的关键因素。miR-451 在 OS 细胞中表达下调，miR-451 的重新表达显著促进了三种 OS 细胞系的细胞失巢凋亡，而抑制 miR-451 可在失巢凋亡条件下保护 HOS 细胞免于失巢凋亡。随后，生物信息学预测和荧光素酶报告基因检测表明，Rab14 是 miR-451 的直接靶点，miR-451 可在 mRNA 和蛋白质水平下调 Rab14。Rab14 的基因沉默重现了 miR-451 对失巢凋亡抗性的作用，Rab14 的恢复在很大程度上消除了 miR-451 的肿瘤抑制功能。最后，miR-451 的过表达显著抑制了 OS 细胞的肺转移。总的来说，我们的研究结果表明，miR-451/Rab14 轴可能是 OS 中抗失巢凋亡的一种新机制。
