Data from Regulation of Apoptosis and Caspase-8 Expression in Neuroblastoma Cells by Isoforms of the <i>IG20</i> Gene

Abstract

<div>Abstract<p>The <i>IG20</i> 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 <i>IG20</i> gene to date have been largely limited to nonneural malignant and nonmalignant cells. In this study, we investigated the expression of alternative splice isoforms of the <i>IG20</i> gene in human neuroblastoma cells. We found that six <i>IG20</i> splice variants (<i>IG20</i>-SVs) were expressed in two human neuroblastoma cell lines (SK-N-SH and SH-SY5Y), highlighted by the expression of two unique splice isoforms (i.e., KIAA0358 and IG20-SV4). Similarly, we found enriched expression of these two <i>IG20</i>-SVs in human neural tissues derived from cerebral cortex, hippocampus, and, to a lesser extent, spinal cord. Using gain-of-function studies and siRNA technology, we determined that these “neural-enriched isoforms” exerted significant and contrasting effects on vulnerability to apoptosis in neuroblastoma cells. Specifically, expression of KIAA0358 exerted a potent antiapoptotic effect in both the SK-N-SH and SH-SY5Y neuroblastoma cell lines, whereas expression of IG20-SV4 had proapoptotic 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 neuroblastoma cells, and that manipulation of <i>IG20</i>-SV expression pattern may represent a potent therapeutic strategy in the therapy of neuroblastoma and perhaps other cancers. [Cancer Res 2008;68(18):7352–61]</p></div>