Choo Zhang'e, Koh Rachel Yu Lin, Wallis Karin, Koh Timothy Jia Wei, Kuick Chik Hong, Sobrado Veronica, Kenchappa Rajappa S, Loh Amos Hong Pheng, Soh Shui Yen, Schlisio Susanne, Chang Kenneth Tou En, Chen Zhi Xiong
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, S117597, Singapore, Singapore.
Ludwig Cancer Research (Stockholm), Karolinska Institutet, SE-17177, Stockholm, Sweden.
Oncotarget. 2016 Jun 7;7(23):34229-39. doi: 10.18632/oncotarget.8748.
Neuroblastoma is an aggressive, relapse-prone childhood tumor of the sympathetic nervous system. Current treatment modalities do not fully exploit the genetic basis between the different molecular subtypes and little is known about the targets discovered in recent mutational and genetic studies. Neuroblastomas with poor prognosis are often characterized by 1p36 deletion, containing the kinesin gene KIF1B. Its beta isoform, KIF1Bβ, is required for NGF withdrawal-dependent apoptosis, mediated by the induction of XIAP-associated Factor 1 (XAF1). Here, we showed that XAF1 low expression correlates with poor survival and disease status. KIF1Bβ deletion results in loss of XAF1 expression, suggesting that XAF1 is indeed a downstream target of KIF1Bβ. XAF1 silencing protects from NGF withdrawal and from KIF1Bβ-mediated apoptosis. Overexpression of XAF1 impairs tumor progression whereas knockdown of XAF1 promotes tumor growth, suggesting that XAF1 may be a candidate tumor suppressor in neuroblastoma and its associated pathway may be important for developing future interventions.
神经母细胞瘤是一种侵袭性强、易复发的儿童交感神经系统肿瘤。目前的治疗方式尚未充分利用不同分子亚型之间的遗传基础，而且对于近期突变和基因研究中发现的靶点了解甚少。预后不良的神经母细胞瘤通常具有1p36缺失的特征，该区域包含驱动蛋白基因KIF1B。其β亚型KIF1Bβ是由XIAP相关因子1（XAF1）诱导介导的、NGF撤除依赖性凋亡所必需的。在此，我们发现XAF1低表达与较差的生存率和疾病状态相关。KIF1Bβ缺失导致XAF1表达丧失，提示XAF1确实是KIF1Bβ的下游靶点。XAF1沉默可保护细胞免受NGF撤除和KIF1Bβ介导的凋亡影响。XAF1过表达会损害肿瘤进展，而XAF1敲低则会促进肿瘤生长，这表明XAF1可能是神经母细胞瘤中的一个候选肿瘤抑制因子，其相关通路可能对未来干预措施的开发具有重要意义。
