Beatson Institute for Cancer Research, Glasgow, United Kingdom.
Cancer Res. 2009 Dec 15;69(24):9219-27. doi: 10.1158/0008-5472.CAN-09-1852.
Largely owing to widespread deployment of microarray analysis, many of the transcriptional events associated with invasive cell migration are becoming clear. However, the transcriptional drives to invasive migration are likely modified by alternative splicing of pre-mRNAs to produce functionally distinct patterns of protein expression. Heterogenous nuclear ribonucleoprotein (hnRNP A2) is a known regulator of alternative splicing that is upregulated in a number of invasive cancer types. Here, we report that although siRNA of hnRNP A2 had little influence on the ability of cells to migrate on plastic surfaces, the splicing regulator was clearly required for cells to move effectively on three-dimensional matrices and to invade into plugs of extracellular matrix proteins. We used exon-tiling microarrays to determine that hnRNP A2 controlled approximately six individual splicing events in a three-dimensional matrix-dependent fashion, one of which influenced invasive migration. Here, we show that alternative splicing of an exon in the 5' untranslated region of a gene termed TP53INP2 is a key event downstream of hnRNP A2 that is necessary for cells to invade the extracellular matrix. Furthermore, we report that the consequences of altered TP53INP2 splicing on invasion are likely mediated via alterations in Golgi complex integrity during migration on three-dimensional matrices.
由于微阵列分析的广泛应用，许多与浸润性细胞迁移相关的转录事件变得清晰起来。然而，浸润性迁移的转录驱动力可能会通过前体 mRNA 的选择性剪接而改变，从而产生功能不同的蛋白质表达模式。异质核核糖核蛋白（hnRNP A2）是一种已知的选择性剪接调节剂，在许多侵袭性癌症类型中上调。在这里，我们报告说，尽管 hnRNP A2 的 siRNA 对细胞在塑料表面上迁移的能力几乎没有影响，但该剪接调节剂显然是细胞在三维基质上有效迁移和侵入细胞外基质蛋白塞所必需的。我们使用外显子平铺微阵列来确定 hnRNP A2 以三维基质依赖性方式控制大约六个单独的剪接事件，其中一个影响浸润性迁移。在这里，我们表明，基因 TP53INP2 的 5'非翻译区外显子的选择性剪接是 hnRNP A2 下游的一个关键事件，对于细胞侵入细胞外基质是必需的。此外，我们报告说，改变 TP53INP2 剪接对入侵的影响可能是通过在三维基质上迁移过程中高尔基体复合体完整性的改变来介导的。
