神经母细胞瘤(NB)是一种严重威胁儿童健康的恶性肿瘤,MYCN的扩增与治疗失败和不良预后相关。这里,我们旨在证明细胞分裂周期27(CDC27)的作用,后期促进复合物的重要核心亚基,及其在NB患者中的临床意义。在功能测定中,我们说明CDC27促进细胞生长,NB细胞在体外和体内的转移和球体形成能力。为了进一步了解潜在的机制,用CDC27siRNA转染SK-N-SH细胞,并进行RNA测序。结果显示,CDC27的下调导致ODC1的表达显著降低,ODC1是MYCN的明确直接靶标。随后,我们进一步说明,抑制ODC1显著减弱CDC27对增殖的促进作用,转移,和NB细胞的球体形成能力,提示CDC27至少部分以ODC1依赖性方式在NB中发挥其生物学行为。此外,CDC27使细胞更容易发生铁死亡,而ODC1的敲除明显逆转了CDC27的促生育作用。总的来说,我们的数据是第一个报道CDC27/ODC1轴促进肿瘤发生,并在NB中充当铁性凋亡的正调节因子,强调CDC27可能代表神经母细胞瘤的新治疗策略和预后生物标志物。
Neuroblastoma (NB) is a devastating malignancy threatening children\'s health, and amplification of MYCN is associated with treatment failure and a poor outcome. Here, we aimed to demonstrate the role of cell division cycle 27 (CDC27), an important core subunit of the anaphase-promoting complex, and its clinical significance in NB patients. In functional assays, we illustrated that CDC27 promoted the cell growth, metastasis and sphere-formation ability of NB cells both in vitro and in vivo. To further understand the potential mechanism, SK-N-SH cells were transfected with CDC27 siRNA, and RNA-sequencing was performed. The results revealed that downregulation of CDC27 led to markedly reduced expression of
ODC1, which is a well-established direct target of MYCN. Subsequently, we further illustrated that suppression of
ODC1 significantly attenuated the promotion effect of CDC27 on the proliferation, metastasis, and sphere-formation ability of NB cells, hinting that CDC27 exerted its biological behavior in NB at least partly in an
ODC1-dependent manner. In addition, CDC27 rendered cells more vulnerable to ferroptosis, while knockdown of
ODC1 markedly reversed the pro-ferroptotic effect of CDC27. Collectively, our data is the first to report that the CDC27/
ODC1 axis promotes tumorigenesis and acts as a positive regulator of ferroptosis in NB, highlighting that CDC27 may represent a novel therapeutic strategy and prognostic biomarker in neuroblastoma.