Aldehyde dehydrogenase activity plays a Key role in the aggressive phenotype of neuroblastoma.
Aldehyde dehydrogenase activity plays a Key role in the aggressive phenotype of neuroblastoma.
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DOI：
10.1186/s12885-016-2820-1
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发表时间：
2016-10-10
期刊：
影响因子：
3.8
通讯作者：
Mühlethaler-Mottet A
中科院分区：
文献类型：
--
作者：
Flahaut M;Jauquier N;Chevalier N;Nardou K;Balmas Bourloud K;Joseph JM;Barras D;Widmann C;Gross N;Renella R;Mühlethaler-Mottet A
通过联合肿瘤起始细胞（TIC）成功靶向神经母细胞瘤（NB）是开发新治疗策略的主要挑战。醛脱氢酶 1 (ALDH1) 同工酶亚家族包括 ALDH1A1、ALDH1A2 和 ALDH1A3，参与视黄酸的合成，并已被确定为多种癌症的功能性干细胞标记物。通过将连续神经球传代与基因表达谱相结合，我们之前已将 ALDH1A2 和 ALDH1A3 鉴定为患者来源的异种移植肿瘤中潜在的 NB TIC 标记物。在这项研究中，我们探讨了 ALDH1 同工酶和相关 ALDH 活性在 NB 攻击特性中的作用。分别使用 ALDEFLUOR™ 试剂盒和实时 PCR 测量 ALDH 活性和 ALDH1A1/A2/A3 表达水平。使用特异性ALDH抑制剂二乙氨基苯甲醛（DEAB）抑制ALDH活性，并通过CRISPR/Cas9技术产生ALDH1A3基因敲除。我们首先证实了神经球传代过程中 NB 细胞系和患者来源的异种移植肿瘤中 ALDH1A2 和 ALDH1A3 mRNA 表达的富集。我们发现 ALDH1A1 高表达与侵袭性较低的 NB 肿瘤和细胞系相关，并与有利的预后因素相关。相反，我们观察到 ALDH1A3 在 NB 细胞系中表达更广泛，并且与较差的生存率和高风险预后因素相关。我们还在各种 NB 细胞系和患者来源的异种移植肿瘤中发现了重要的 ALDH 活性。用二乙氨基苯甲醛 (DEAB) 特异性抑制 ALDH 活性，导致 NB 细胞克隆性和 TIC 自我更新潜力大幅降低，并部分增强 NB 细胞对 4-羟基环磷酰胺的敏感性。最后，通过 CRISPR/Cas9 基因编辑特异性敲除 ALDH1A3 降低了 NB 细胞克隆形成性，并介导了细胞类型依赖性的 TIC 自我更新特性抑制。我们的数据共同揭示了 ALDH 酶活性在 NB 侵袭性和 4-羟基环磷酰胺抗性中的参与，并表明特定的 ALDH1A3 同工酶增加了一部分 NB 细胞的侵袭能力。本文的在线版本 (doi:10.1186/s12885-016-2820-1) 包含补充材料，可供授权用户使用。
The successful targeting of neuroblastoma (NB) by associating tumor-initiating cells (TICs) is a major challenge in the development of new therapeutic strategies. The subfamily of aldehyde dehydrogenases 1 (ALDH1) isoenzymes, which comprises ALDH1A1, ALDH1A2, and ALDH1A3, is involved in the synthesis of retinoic acid, and has been identified as functional stem cell markers in diverse cancers. By combining serial neurosphere passages with gene expression profiling, we have previously identified ALDH1A2 and ALDH1A3 as potential NB TICs markers in patient-derived xenograft tumors. In this study, we explored the involvement of ALDH1 isoenzymes and the related ALDH activity in NB aggressive properties. ALDH activity and ALDH1A1/A2/A3 expression levels were measured using the ALDEFLUOR™ kit, and by real-time PCR, respectively. ALDH activity was inhibited using the specific ALDH inhibitor diethylaminobenzaldehyde (DEAB), and ALDH1A3 gene knock-out was generated through the CRISPR/Cas9 technology. We first confirmed the enrichment of ALDH1A2 and ALDH1A3 mRNA expression in NB cell lines and patient-derived xenograft tumors during neurosphere passages. We found that high ALDH1A1 expression was associated with less aggressive NB tumors and cell lines, and correlated with favorable prognostic factors. In contrast, we observed that ALDH1A3 was more widely expressed in NB cell lines and was associated with poor survival and high-risk prognostic factors. We also identified an important ALDH activity in various NB cell lines and patient-derived xenograft tumors. Specific inhibition of ALDH activity with diethylaminobenzaldehyde (DEAB) resulted in a strong reduction of NB cell clonogenicity, and TIC self-renewal potential, and partially enhanced NB cells sensitivity to 4-hydroxycyclophosphamide. Finally, the specific knock-out of ALDH1A3 via CRISPR/Cas9 gene editing reduced NB cell clonogenicity, and mediated a cell type-dependent inhibition of TIC self-renewal properties. Together our data uncover the participation of ALDH enzymatic activity in the aggressive properties and 4-hydroxycyclophosphamide resistance of NB, and show that the specific ALDH1A3 isoenzyme increases the aggressive capacities of a subset of NB cells. The online version of this article (doi:10.1186/s12885-016-2820-1) contains supplementary material, which is available to authorized users.
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影响因子：
7.2
作者：
Flahaut, M;Mühlethaler-Mottet, A;Gross, N
通讯作者：
Gross, N
影响因子：
2.7
作者：
Jia J;Parikh H;Xiao W;Hoskins JW;Pflicke H;Liu X;Collins I;Zhou W;Wang Z;Powell J;Thorgeirsson SS;Rudloff U;Petersen GM;Amundadottir LT
通讯作者：
Amundadottir LT
影响因子：
--
作者：
Montavon G;Jauquier N;Coulon A;Peuchmaur M;Flahaut M;Bourloud KB;Yan P;Delattre O;Sommer L;Joseph JM;Janoueix-Lerosey I;Gross N;Mühlethaler-Mottet A
通讯作者：
Mühlethaler-Mottet A
影响因子：
10.6
作者：
Abdullah LN;Chow EK
通讯作者：
Chow EK
影响因子：
5.2
作者：
Luo, Yuchun;Dallaglio, Katiuscia;Chen, Ying;Robinson, William A.;Robinson, Steven E.;McCarter, Martin D.;Wang, Jianbin;Gonzalez, Rene;Thompson, David C.;Norris, David A.;Roop, Dennis R.;Vasiliou, Vasilis;Fujita, Mayumi
通讯作者：
Fujita, Mayumi