Regulation of apoptosis and caspase-8 expression in neuroblastoma cells by isoforms of the IG20 gene.
Regulation of apoptosis and caspase-8 expression in neuroblastoma cells by isoforms of the IG20 gene.
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DOI：
10.1158/0008-5472.can-07-6311
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发表时间：
2008-09-15
期刊：
影响因子：
11.2
通讯作者：
Meriggioli MN
中科院分区：
文献类型：
--
作者：
Li LC;Sheng JR;Mulherkar N;Prabhakar BS;Meriggioli MN
IG 20基因经历选择性剪接，导致六种推定的剪接变体的差异表达。其中四种（IG 20 pa、MADD、IG 20-SV 2和DENN-SV）在几乎所有的人体组织中表达。然而，迄今为止，研究IG 20基因的选择性剪接的研究主要限于非神经恶性和非恶性细胞。在这项研究中，我们研究了IG 20基因的选择性剪接异构体在人神经母细胞瘤（NB）细胞中的表达。我们发现六种IG 20剪接变体（IG 20-SV）在两种人NB细胞系（SK-N-SH和SH-SY 5 Y）中表达，突出显示了两种独特的剪接异构体，即KIAA 0358和IG 20-SV 4。类似地，我们发现这两种IG 20-SV在源自大脑皮层、海马和较小程度上脊髓的人神经组织中富集表达。利用获得的功能研究和siRNA技术，我们确定，这些“神经富集亚型”发挥显着的和对比的影响，对NB细胞凋亡的脆弱性。具体地，KIAA 0358的表达在SK-N-SH和SH-SY 5 Y NB细胞系中均发挥有效的抗凋亡作用，而IG 20-SV 4的表达具有与这些细胞中的半胱天冬酶-8的活化直接相关的促凋亡作用，这些细胞具有最小的或不存在的组成型半胱天冬酶-8表达。这些数据表明，这些神经富集的IG 20-SV的表达模式调节某些NB细胞中半胱天冬酶-8的表达和活化，并且IG 20-SV表达模式的操纵可能代表神经母细胞瘤以及可能的其他癌症的治疗中的有效治疗策略。
The IG20 gene undergoes alternative splicing resulting in the differential expression of six putative splice variants. Four of these (IG20pa, MADD, IG20-SV2 and DENN-SV) are expressed in virtually all human tissues. However, investigations examining alternative splicing of the IG20 gene to date have been largely limited to non-neural malignant and non-malignant cells. In this study, we investigated the expression of alternative splice isoforms of the IG20 gene in human neuroblastoma (NB) cells. We found that six IG20 splice variants (IG20-SVs) were expressed in two human NB cell lines (SK-N-SH and SH-SY5Y), highlighted by the expression of two unique splice isoforms, namely KIAA0358 and IG20-SV4. Similarly, we found enriched expression of these two IG20-SVs in human neural tissues derived from cerebral cortex, hippocampus, and, to a lesser extent, spinal cord. Utilizing gain of function studies and siRNA technology, we determined that these “neural-enriched isoforms” exerted significant and contrasting effects on vulnerability to apoptosis in NB cells. Specifically, expression of KIAA0358 exerted a potent anti-apoptotic effect in both the SK-N-SH and SH-SY5Y NB cell lines, while expression of IG20-SV4 had pro-apoptotic effects directly related to the activation of caspase-8 in these cells, which have minimal or absent constitutive caspase-8 expression. These data indicate that the pattern of expression of these neural-enriched IG20-SVs regulates the expression and activation of caspase-8 in certain NB cells, and that manipulation of IG20-SV expression pattern may represent a potent therapeutic strategy in the therapy of neuroblastoma, and perhaps other cancers.