Department of Epidemiology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
Int J Oncol. 2015 Mar;46(3):1089-98. doi: 10.3892/ijo.2014.2801. Epub 2014 Dec 17.
Despite the introduction of 13-cis-retinoic acid (13-cis-RA) into the current chemotherapy, more than half of high-risk neuroblastoma patients have experienced tumor relapses driven by chemoresistant cancer stem cells (CSCs) that can be isolated by their ability to grow as spheres. Although aldehyde dehydrogenase (ALDH) has been used to characterize CSCs in certain cancers, ALDH remains elusive in neuroblastoma. In the present study, we determined ALDH activity and expression of its 19 isoforms in spheres and parental cells of neuroblastoma. ALDH activity and several ALDH isoforms were consistently induced in spheres of different neuroblastoma cells. While ALDH1A2, ALDH1L1 and ALDH3B2 expression was consistently induced in spheres and associated with the sphere and colony formation, only ALDH1A2 expression was significantly correlated with the poor prognosis of neuroblastoma patients. ALDH1A2 expression was further associated with the growth and undifferentiation of neuroblastoma xenografts and the resistance of neuroblastoma cells to 13-cis-RA. These results suggest that ALDH1A2 is involved in the regulation of CSC properties in neuroblastoma.
尽管已经将 13-顺式维甲酸（13-cis-RA）引入当前的化疗中，但仍有超过一半的高危神经母细胞瘤患者经历了肿瘤复发，这些肿瘤是由能够以球体形式生长的耐药性癌症干细胞（CSC）驱动的。尽管醛脱氢酶（ALDH）已被用于某些癌症的 CSC 特征鉴定，但在神经母细胞瘤中，ALDH 仍然难以捉摸。在本研究中，我们确定了神经母细胞瘤球体和亲本细胞中 ALDH 的活性和 19 种同工酶的表达。ALDH 活性和几种 ALDH 同工酶在不同神经母细胞瘤细胞的球体中持续诱导。虽然 ALDH1A2、ALDH1L1 和 ALDH3B2 的表达在球体中持续诱导，并与球体和集落形成相关，但只有 ALDH1A2 的表达与神经母细胞瘤患者的不良预后显著相关。ALDH1A2 的表达进一步与神经母细胞瘤异种移植物的生长和未分化以及神经母细胞瘤细胞对 13-cis-RA 的耐药性相关。这些结果表明，ALDH1A2 参与了神经母细胞瘤中 CSC 特性的调节。
