Hox-C9 activates the intrinsic pathway of apoptosis and is associated with spontaneous regression in neuroblastoma.
Hox-C9 activates the intrinsic pathway of apoptosis and is associated with spontaneous regression in neuroblastoma.
复制标题
DOI：
10.1038/cddis.2013.84
复制
发表时间：
2013-04-11
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
神经母细胞瘤是交感神经系统的胚胎性恶性肿瘤。在一部分患者中观察到神经母细胞瘤的自发消退和分化，并已被认为代表胎儿神经母细胞生理分子程序的延迟激活。同源异型盒基因是一类重要的转录因子家族，在胚胎发育的形态发生和细胞分化中起着重要作用。在这项研究中，我们证明了大多数人HOX I类同源框基因的表达与神经母细胞瘤的临床协变量显着相关，使用649个原发性肿瘤的微阵列表达数据。此外，HOX基因表达为基础的分类预测神经母细胞瘤患者的结果独立于年龄，阶段和MYCN扩增状态。在所有HOX基因中，HOXC 9表达与有利的预后标志物最显著相关。最值得注意的是，HOXC 9表达升高与婴儿神经母细胞瘤的自发消退显著相关。HOXC 9在三种神经母细胞瘤细胞系中的重新表达导致细胞活力显著降低，并且在神经母细胞瘤异种移植物中几乎完全消除肿瘤生长。神经母细胞瘤生长停滞与程序性细胞死亡的诱导有关，如由亚G1级分的增加和磷脂酰丝氨酸向外膜的易位所示。程序性细胞死亡与细胞色素c从线粒体释放到胞质溶胶中以及半胱天冬酶内在级联的激活相关，表明HOXC 9再表达触发了内在凋亡途径。总的来说，我们的研究结果显示了HOX基因表达对神经母细胞瘤预后的强烈影响，并可能指向Hox-C9在神经母细胞瘤自发消退中的作用。
Neuroblastoma is an embryonal malignancy of the sympathetic nervous system. Spontaneous regression and differentiation of neuroblastoma is observed in a subset of patients, and has been suggested to represent delayed activation of physiologic molecular programs of fetal neuroblasts. Homeobox genes constitute an important family of transcription factors, which play a fundamental role in morphogenesis and cell differentiation during embryogenesis. In this study, we demonstrate that expression of the majority of the human HOX class I homeobox genes is significantly associated with clinical covariates in neuroblastoma using microarray expression data of 649 primary tumors. Moreover, a HOX gene expression-based classifier predicted neuroblastoma patient outcome independently of age, stage and MYCN amplification status. Among all HOX genes, HOXC9 expression was most prominently associated with favorable prognostic markers. Most notably, elevated HOXC9 expression was significantly associated with spontaneous regression in infant neuroblastoma. Re-expression of HOXC9 in three neuroblastoma cell lines led to a significant reduction in cell viability, and abrogated tumor growth almost completely in neuroblastoma xenografts. Neuroblastoma growth arrest was related to the induction of programmed cell death, as indicated by an increase in the sub-G1 fraction and translocation of phosphatidylserine to the outer membrane. Programmed cell death was associated with the release of cytochrome c from the mitochondria into the cytosol and activation of the intrinsic cascade of caspases, indicating that HOXC9 re-expression triggers the intrinsic apoptotic pathway. Collectively, our results show a strong prognostic impact of HOX gene expression in neuroblastoma, and may point towards a role of Hox-C9 in neuroblastoma spontaneous regression.
登录
查看更多内容
影响因子：
10.3
作者：
Asgharzadeh, Shahab;Pique-Regi, Roger;Seeger, Robert C.
通讯作者：
Seeger, Robert C.
影响因子：
6.4
作者：
Coco, Simona;Theissen, Jessica;Tonini, Gian Paolo
通讯作者：
Tonini, Gian Paolo
影响因子：
45.3
作者：
BRODEUR, GM;PRITCHARD, J;VOUTE, PA
通讯作者：
VOUTE, PA
影响因子：
11.5
作者：
Fischer, Matthias;Oberthuer, Andre;Berthold, Frank
通讯作者：
Berthold, Frank
影响因子：
12.4
作者：
Kashkar, H;Krönke, M;Jürgensmeier, JM
通讯作者：
Jürgensmeier, JM