Department of Pediatrics and the Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA, USA.
Children's Hospital of Los Angeles, University of Southern California, Los Angeles, CA, USA.
Oncogene. 2024 Apr;43(16):1203-1213. doi: 10.1038/s41388-024-02980-y. Epub 2024 Feb 27.
Neuroblastoma is the most common extracranial malignant tumor of childhood, accounting for 15% of all pediatric cancer deaths. Despite significant advances in our understanding of neuroblastoma biology, five-year survival rates for high-risk disease remain less than 50%, highlighting the importance of identifying novel therapeutic targets to combat the disease. MYCN amplification is the most frequent and predictive molecular aberration correlating with poor outcome in neuroblastoma. N-Myc is a short-lived protein primarily due to its rapid proteasomal degradation, a potentially exploitable vulnerability in neuroblastoma. AF1q is an oncoprotein with established roles in leukemia and solid tumor progression. It is normally expressed in brain and sympathetic neurons and has been postulated to play a part in neural differentiation. However, no role for AF1q in tumors of neural origin has been reported. In this study, we found AF1q to be a universal marker of neuroblastoma tumors. Silencing AF1q in neuroblastoma cells caused proteasomal degradation of N-Myc through Ras/ERK and AKT/GSK3β pathways, activated p53 and blocked cell cycle progression, culminating in cell death via the intrinsic apoptotic pathway. Moreover, silencing AF1q attenuated neuroblastoma tumorigenicity in vivo signifying AF1q's importance in neuroblastoma oncogenesis. Our findings reveal AF1q to be a novel regulator of N-Myc and potential therapeutic target in neuroblastoma.
神经母细胞瘤是儿童最常见的颅外恶性肿瘤，占儿童癌症死亡人数的 15%。尽管我们对神经母细胞瘤生物学的理解有了显著进展，但高危疾病的五年生存率仍低于 50%，这凸显了确定新的治疗靶点来对抗该疾病的重要性。MYCN 扩增是与神经母细胞瘤预后不良最相关的最常见和最具预测性的分子异常。N-Myc 是一种短寿命的蛋白质，主要是由于其快速的蛋白酶体降解，这是神经母细胞瘤中一个潜在可利用的脆弱性。AF1q 是一种具有白血病和实体瘤进展中确立作用的癌蛋白。它通常在大脑和交感神经元中表达，并被假设在神经分化中发挥作用。然而，尚未报道 AF1q 在神经来源的肿瘤中的作用。在这项研究中，我们发现 AF1q 是神经母细胞瘤肿瘤的通用标志物。在神经母细胞瘤细胞中沉默 AF1q 通过 Ras/ERK 和 AKT/GSK3β 途径导致 N-Myc 的蛋白酶体降解，激活 p53 并阻止细胞周期进程，最终通过内在凋亡途径导致细胞死亡。此外，沉默 AF1q 减弱了体内神经母细胞瘤的致瘤性，表明 AF1q 在神经母细胞瘤发生中具有重要作用。我们的研究结果表明，AF1q 是 N-Myc 的一种新的调节剂，也是神经母细胞瘤的潜在治疗靶点。
