University of Hawaii at Hilo, The Daniel K. Inouye College of Pharmacy, Hilo, HI 96720, USA.
FEBS Open Bio. 2014 Oct 30;4:966-75. doi: 10.1016/j.fob.2014.10.012. eCollection 2014.
Neuroblastoma is an extra-cranial solid cancer in children. MYCN gene amplification is a prognostic indicator of poor outcome in neuroblastoma. Recent studies have shown that the multiple steps involved in cell migration are dependent on the availability of intracellular calcium (Ca(2+)). Although significant advances have been made in understanding the role of Ca(2+) during migration, little has been achieved towards understanding its impact on the progression of diseases such as cancer. Interestingly, previous studies showed that cancer cell migration is regulated by TRPM7, a calcium-permeable ion channel. The objective of the current study was to elucidate the mechanism by which MycN promotes NB cell migration and the mechanism regulating TRPM7 expression. The results showed that MycN increased TRPM7 expression, induced TRPM7 channel activity, increased intracellular Ca(2+) signaling, and promoted cell migration in NB cells. The results also showed that inhibition or down-regulation of ornithine decarboxylase (ODC) inhibited TRPM7 expression, a process that was reversed by spermidine. Overall, this study provides evidence that MycN promotes TRPM7 expression and cell migration through a mechanism that involves ODC synthesis of polyamines.
神经母细胞瘤是儿童的颅外实体瘤。MYCN 基因扩增是神经母细胞瘤预后不良的一个预示指标。最近的研究表明，细胞迁移所涉及的多个步骤依赖于细胞内钙（Ca(2+)）的可用性。尽管在理解迁移过程中 Ca(2+)的作用方面取得了重大进展，但在理解其对癌症等疾病进展的影响方面却鲜有进展。有趣的是，先前的研究表明，钙通透性离子通道 TRPM7 调控癌细胞迁移。本研究的目的是阐明 MycN 促进 NB 细胞迁移的机制以及调节 TRPM7 表达的机制。结果表明，MycN 增加了 TRPM7 的表达，诱导了 TRPM7 通道活性，增加了细胞内 Ca(2+)信号，并促进了 NB 细胞的迁移。结果还表明，抑制或下调鸟氨酸脱羧酶（ODC）抑制了 TRPM7 的表达，这一过程可被亚精胺逆转。总的来说，这项研究提供了证据表明，MycN 通过涉及多胺的 ODC 合成来促进 TRPM7 表达和细胞迁移。
