Qiao Jingbo, Rellinger Eric J, Kim Kwang Woon, Powers Camille M, Lee Sora, Correa Hernan, Chung Dai H
Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Oncotarget. 2019 Aug 20;10(49):5028-5040. doi: 10.18632/oncotarget.27096.
The lost expression of α-catenin has been found in cancers, and reinstalling α-catenin inhibits tumor growth. Here we hypothesized that the α-N-catenin, a homologous member of α-catenin and neural-specific expressed, functions as a novel tumor suppressor in neural crest-derived tumor, neuroblastoma. We correlated CTNNA2 (encodes α-N-catenin) expression to neuroblastoma disease relapse-free survival probability using publicly accessible human neuroblastoma datasets in R2 platform. The result showed that it negatively correlated to relapse-free survival probability significantly in patients with neuroblastoma with non-MYCN amplified tumor. Conversely, overexpressing CTNNA2 suppressed the neuroblastoma cell proliferation as measuring by the clonogenesis, inhibited anchorage-independent growth with soft agar colony formation assay. Forced expression of CTNNA2 decreased cell migration and invasion. Further, overexpression of CTNNA2 reduced the secretion of angiogenic factor IL-8 and HUVEC tubule formation. Our results show, for the first time, that α-N-catenin is a tumor suppressor in neuroblastoma cells. These findings were further corroborated with tumor xenograft study, in which α-N-catenin inhibited tumor growth and reduced tumor blood vessel formation. Interestingly, this is only observed in SK-N-AS xenografts lacking MYCN expression, and not in BE(2)-C xenografts with MYCN amplification. Mechanistically, α-N-catenin attenuated NF-κB responsive genes by inhibiting NF-κB transcriptional activity. In conclusion, these data demonstrate that α-N-catenin is a tumor suppressor in non-MYCN-amplified neuroblastomas and it inhibits NF-κB signaling pathway to suppress tumor growth in human neuroblastomas. Therefore, restoring the expression of α-N-catenin can be a novel therapeutic approach for neuroblastoma patients who have the deletion of CTNNA2 and lack of MYCN amplification.
α-连环蛋白的表达缺失已在癌症中被发现，重新表达α-连环蛋白可抑制肿瘤生长。在此，我们推测α-N-连环蛋白是α-连环蛋白的同源成员且在神经中特异性表达，它在神经嵴来源的肿瘤——神经母细胞瘤中作为一种新型肿瘤抑制因子发挥作用。我们在R2平台上使用公开可用的人类神经母细胞瘤数据集，将CTNNA2（编码α-N-连环蛋白）的表达与神经母细胞瘤疾病无复发生存概率相关联。结果显示，在非MYCN扩增肿瘤的神经母细胞瘤患者中，它与无复发生存概率呈显著负相关。相反，过表达CTNNA2可抑制神经母细胞瘤细胞增殖（通过克隆形成测定），通过软琼脂集落形成试验抑制非锚定依赖性生长。强制表达CTNNA2可减少细胞迁移和侵袭。此外，CTNNA2的过表达减少了血管生成因子IL-8的分泌以及人脐静脉内皮细胞（HUVEC）的小管形成。我们的数据首次表明，α-N-连环蛋白是神经母细胞瘤细胞中的一种肿瘤抑制因子。这些发现通过肿瘤异种移植研究得到进一步证实，其中α-N-连环蛋白抑制肿瘤生长并减少肿瘤血管形成。有趣的是，这仅在缺乏MYCN表达的SK-N-AS异种移植中观察到，而在具有MYCN扩增的BE(2)-C异种移植中未观察到。从机制上讲，α-N-连环蛋白通过抑制NF-κB转录活性减弱NF-κB反应性基因。总之，这些数据表明α-N-连环蛋白是未扩增MYCN的神经母细胞瘤中的一种肿瘤抑制因子，并且它抑制NF-κB信号通路以抑制人类神经母细胞瘤中的肿瘤生长。因此，恢复α-N-连环蛋白的表达可能是针对CTNNA2缺失且缺乏MYCN扩增的神经母细胞瘤患者的一种新型治疗方法。
