Medical School, Nantong University, 19 Qixiu Road, Nantong, 226001, Jiangsu, People's Republic of China.
Neurochem Res. 2023 Jul;48(7):2116-2128. doi: 10.1007/s11064-023-03882-3. Epub 2023 Feb 16.
Neuroblastoma (NB) is a pediatric malignancy that arises in the peripheral nervous system, and the prognosis in the high-risk group remains dismal, despite the breakthroughs in multidisciplinary treatments. The oral treatment with 13-cis-retinoic acid (RA) after high-dose chemotherapy and stem cell transplant has been proven to reduce the incidence of tumor relapse in children with high-risk neuroblastoma. However, many patients still have tumors relapsed following retinoid therapy, highlighting the need for the identification of resistant factors and the development of more effective treatments. Herein, we sought to investigate the potential oncogenic roles of the tumor necrosis factor (TNF) receptor-associated factor (TRAF) family in neuroblastoma and explore the correlation between TRAFs and retinoic acid sensitivity. We discovered that all TRAFs were efficiently expressed in neuroblastoma, but TRAF4, in particular, was found to be strongly expressed. The high expression of TRAF4 was associated with a poor prognosis in human neuroblastoma. The inhibition of TRAF4, rather than other TRAFs, improved retinoic acid sensitivity in two human neuroblastoma cell lines, SH-SY5Y and SK-N-AS cells. Further in vitro studies indicated that TRAF4 suppression induced retinoic acid-induced cell apoptosis in neuroblastoma cells, probably by upregulating the expression of Caspase 9 and AP1 while downregulating Bcl-2, Survivin, and IRF-1. Notably, the improved anti-tumor effects from the combination of TRAF4 knockdown and retinoic acid were confirmed in vivo using the SK-N-AS human neuroblastoma xenograft model. In conclusion, the highly expressed TRAF4 might be implicated in developing resistance to retinoic acid treatment in neuroblastoma, and the combination therapy with retinoic acid and TRAF4 inhibition may offer significant therapeutic advantages in the treatment of relapsed neuroblastoma.
神经母细胞瘤（NB）是一种起源于外周神经系统的儿科恶性肿瘤，尽管多学科治疗取得了突破，但高危组的预后仍然不佳。高剂量化疗和干细胞移植后口服 13-顺式维甲酸（RA）已被证明可降低高危神经母细胞瘤患儿肿瘤复发的发生率。然而，许多患者在接受维甲酸治疗后仍有肿瘤复发，这突出表明需要确定耐药因素并开发更有效的治疗方法。在此，我们试图研究肿瘤坏死因子（TNF）受体相关因子（TRAF）家族在神经母细胞瘤中的潜在致癌作用，并探讨 TRAFs 与维甲酸敏感性之间的相关性。我们发现所有 TRAFs 在神经母细胞瘤中均有效表达，但 TRAF4 表达特别强。TRAF4 的高表达与人类神经母细胞瘤的不良预后相关。抑制 TRAF4（而不是其他 TRAFs）可改善两种人类神经母细胞瘤细胞系（SH-SY5Y 和 SK-N-AS 细胞）对维甲酸的敏感性。进一步的体外研究表明，TRAF4 抑制可诱导神经母细胞瘤细胞中维甲酸诱导的细胞凋亡，可能通过上调 Caspase 9 和 AP1 的表达，同时下调 Bcl-2、Survivin 和 IRF-1 的表达。值得注意的是，在 SK-N-AS 人神经母细胞瘤异种移植模型中，证实了 TRAF4 敲低与维甲酸联合使用可增强体内抗肿瘤作用。总之，高表达的 TRAF4 可能参与了神经母细胞瘤对维甲酸治疗的耐药性发展，维甲酸和 TRAF4 抑制联合治疗可能为复发性神经母细胞瘤的治疗提供显著的治疗优势。
