TRAF4 Silencing Induces Cell Apoptosis and Improves Retinoic Acid Sensitivity in Human Neuroblastoma
TRAF4 Silencing Induces Cell Apoptosis and Improves Retinoic Acid Sensitivity in Human Neuroblastoma
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DOI：
10.1007/s11064-023-03882-3
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发表时间：
2023-02-16
影响因子：
4.4
通讯作者：
Zeng, Xuhui
中科院分区：
文献类型：
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作者：
Gu, Yayun;Zhong, Kun;Zeng, Xuhui
神经母细胞瘤（NB）是一种发生于周围神经系统的儿科恶性肿瘤，尽管多学科治疗取得了突破，但高危人群的预后仍然令人沮丧。大剂量化疗和干细胞移植后口服13-顺式维甲酸（RA）已被证明可以降低高危神经母细胞瘤儿童肿瘤复发的发生率。然而，许多患者在类视黄醇治疗后肿瘤仍然复发，这凸显了识别耐药因素和开发更有效治疗方法的必要性。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TRAF与视黄酸敏感性之间的相关性。我们发现所有 TRAF 在神经母细胞瘤中均有效表达，但特别是 TRAF4 被发现强烈表达。 TRAF4的高表达与人神经母细胞瘤的不良预后相关。 TRAF4 的抑制（而不是其他 TRAF）提高了两种人神经母细胞瘤细胞系 SH-SY5Y 和 SK-N-AS 细胞中的视黄酸敏感性。进一步的体外研究表明，TRAF4 抑制可能通过上调 Caspase 9 和 AP1 的表达，同时下调 Bcl-2、Survivin 和 IRF-1 的表达，诱导视黄酸诱导的神经母细胞瘤细胞凋亡。值得注意的是，使用 SK-N-AS 人神经母细胞瘤异种移植模型在体内证实了 TRAF4 敲低和视黄酸组合的抗肿瘤效果的改善。总之，高表达的TRAF4可能与神经母细胞瘤对视黄酸治疗产生耐药性有关，视黄酸和TRAF4抑制剂的联合治疗可能在治疗复发性神经母细胞瘤中提供显着的治疗优势。
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.