ALKR1275Q perturbs extracellular matrix, enhances cell invasion and leads to the development of neuroblastoma in cooperation with MYCN.
ALKR1275Q perturbs extracellular matrix, enhances cell invasion and leads to the development of neuroblastoma in cooperation with MYCN.
复制标题
ALKR1275Q 扰乱细胞外基质，增强细胞侵袭，并与 MYCN 协同导致神经母细胞瘤的发展。
DOI：
10.1038/onc.2015.519
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Honda H.
中科院分区：
文献类型：
--
作者：
Ueda T;Nakata Y;Yamasaki N;Oda H;Sentani K;Kanai A;Onishi N;Ikeda K;Sera Y;Honda ZI;Tanaka K;Sata M;Ogawa S;Yasui W;Saya H;Takita J;Honda H.
MYCN的过表达是神经母细胞瘤（NB）的标志。ALK R1275 Q是ALK（间变性淋巴瘤激酶）的激活突变，已在散发性和家族性NB患者中发现。在本报告中，我们证明了ALK R1275 Q基因敲入、MYCN转基因复合小鼠发生了NB，且完全无突变。转录组分析显示，ALK R1275 Q在原代神经元细胞和NB肿瘤中全面下调细胞外基质（ECM）和基底膜（BM）相关基因的表达。因此，与MYCN肿瘤相比，ALK R1275 Q/MYCN肿瘤显示ECM/BM相关蛋白的表达降低。此外，在MYCN转导后，ALK R1275 Q表达神经元细胞表现出迁移和侵袭活性增加。在ALK R1275 Q/MYCN小鼠中证实了一致性、增强的侵袭和转移。这些结果共同表明，ALK R1275 Q通过损害正常ECM/BM完整性和增强肿瘤生长和扩散，赋予过表达MYCN的神经元细胞恶性潜能。此外，我们发现克唑替尼（一种ALK抑制剂）几乎完全抑制了同种异体移植模型中ALK R1275 Q/MYCN肿瘤的生长。我们的研究结果为突变的ALK和过表达的MYCN在NB发病机制中的协同机制提供了见解，并证明了克唑替尼对ALK R1275 Q阳性肿瘤的有效性。
Overexpression of MYCN is a hallmark of neuroblastoma (NB). ALK R1275Q, an activating mutation of ALK (anaplastic lymphoma kinase), has been found in sporadic and familial NB patients. In this report, we demonstrated that ALK R1275Q knock-in, MYCN transgenic compound mice developed NB with complete penetrance. Transcriptome analysis revealed that ALK R1275Q globally downregulated the expression of extracellular matrix (ECM)-and basement membrane (BM)-associated genes in both primary neuronal cells and NB tumors. Accordingly, ALK R1275Q/MYCN tumors exhibited reduced expression of ECM/BM-related proteins as compared with MYCN tumors. In addition, on MYCN transduction, ALK R1275Q-expressing neuronal cells exhibited increased migratory and invasive activities. Consistently, enhanced invasion and metastasis were demonstrated in ALK R1275Q/MYCN mice. These results collectively indicate that ALK R1275Q confers a malignant potential on neuronal cells that overexpress MYCN by impairing normal ECM/BM integrity and enhancing tumor growth and dissemination. Moreover, we found that crizotinib, an ALK inhibitor, almost completely inhibited the growth of ALK R1275Q/MYCN tumors in an allograft model. Our findings provided insights into the cooperative mechanism of the mutated ALK and overexpressed MYCN in the pathogenesis of NB and demonstrated the effectiveness of crizotinib on ALK R1275Q-positive tumors.