Combinatorial regulation of neuroblastoma tumor progression by N-Myc and hypoxia inducible factor HIF-1alpha.
Combinatorial regulation of neuroblastoma tumor progression by N-Myc and hypoxia inducible factor HIF-1alpha.
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DOI：
10.1158/0008-5472.can-10-0740
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发表时间：
2010-12-15
期刊：
影响因子：
11.2
通讯作者：
Simon MC
中科院分区：
文献类型：
--
作者：
Qing G;Skuli N;Mayes PA;Pawel B;Martinez D;Maris JM;Simon MC
在人类神经母细胞瘤中，MYCN基因的扩增预示着不良的预后和对治疗的抵抗。由于缺氧主要通过两种结构相关的缺氧诱导因子HIF-1α和HIF-2α导致侵袭性肿瘤表型，因此我们检测了MYCN扩增的神经母细胞瘤细胞中的缺氧反应。我们在此证明，与没有MYCN扩增的样本相比，HIF-1α而不是HIF-2α优先在MYCN扩增的神经母细胞瘤细胞和原发性肿瘤中表达。我们的研究结果表明，N-Myc和HIF-1α之间的相互作用在神经母细胞瘤中起着关键作用。例如，高水平的N-Myc覆盖HIF-1α对细胞周期进程的抑制，使其能够在缺氧条件下继续增殖。此外，HIF-1α和N-Myc通过激活多个糖酵解基因的转录，对神经母细胞瘤中的瓦尔堡效应（有氧糖酵解）是必需的。值得注意的是，与没有MYCN扩增的肿瘤相比，磷酸甘油酸激酶1（PGK 1）、己糖激酶2（HK 2）和乳酸脱氢酶A（LDHA）的表达在MYCN扩增的神经母细胞瘤中均显著更高。有趣的是，MYCN扩增的神经母细胞瘤细胞对LDHA酶活性“上瘾”，因为其消耗完全抑制体内肿瘤发生。因此，我们的研究结果提供了解释MYCN扩增的神经母细胞瘤细胞如何对抗缺氧应激以及缺氧如何通过N-Myc和HIF-1α的组合作用促进神经母细胞瘤侵袭性的机制见解。这些结果还表明LDHA代表了神经母细胞瘤治疗的新的、易处理的靶点。
In human neuroblastoma, amplification of the MYCN gene predicts poor prognosis and resistance to therapy. Because hypoxia contributes to aggressive tumor phenotypes, predominantly via two structurally related hypoxia inducible factors, HIF-1α and HIF-2α, we examined hypoxia responses in MYCN amplified neuroblastoma cells. We demonstrate here that HIF-1α, but not HIF-2α, is preferentially expressed in both MYCN amplified neuroblastoma cells and primary tumors in comparison to samples without MYCN amplification. Our results showed that interplay between N-Myc and HIF-1α plays critical roles in neuroblastoma. For example, high levels of N-Myc override HIF-1α inhibition of cell cycle progression, enabling continued proliferation under hypoxia. Furthermore, both HIF-1α and N-Myc are essential for the Warburg effect (aerobic glycolysis) in neuroblastomas by activating the transcription of multiple glycolytic genes. Of note, expression of Phosphoglycerate Kinase 1 (PGK1), Hexokinase 2 (HK2) and Lactate Dehydrogenase A (LDHA), were each significantly higher in MYCN amplified neuroblastomas compared to tumors without MYCN amplification. Interestingly, MYCN amplified neuroblastoma cells are “addicted” to LDHA enzymatic activity, as its depletion completely inhibits tumorigenesis in vivo. Thus, our results provide mechanistic insights explaining how MYCN amplified neuroblastoma cells contend with hypoxic stress and paradoxically how hypoxia contributes to neuroblastoma aggressiveness through combinatorial effects of N-Myc and HIF-1α. These results also suggest LDHA represents a novel, pharmacologically tractable target for neuroblastoma therapeutics.