The Role of Aberrant Splicing of EVl1 in Ovarian Cancer Pathophysiology

描述（由申请人提供）：使用高分辨率比较基因组杂交（CGH）阵列分析235例卵巢癌，我们将卵巢癌中拷贝数增加的最常见区域缩小到3q26.2的约3.2 MB宽区域。对该区域内基因的真实的时间PCR表明EVI 1（亲嗜性病毒整合位点-1）和基因间MDS 1/EVI 1融合转录物是该区域内最高度扩增的转录物。此外，EVI 1在>90%的肿瘤中异常剪接（Del 190 -515）。MDS 1/EVI 1和EVI 1改变卵巢上皮细胞的增殖、运动、衰老和信号传导。此外，MDS 1/EVI 1水平的增加与良好的预后相关，而EVI 1Del 190 -515与不良预后相关。因此，我们的数据表明，EVI 1，MDS 1/EVI 1及其剪接形式在肿瘤发生和发展过程中发挥不同的作用，这取决于细胞环境。患者结局可能取决于EVI 1剪接变异体的相对水平。EVI 1最近与细胞存活和转化生长因子（TGF β、TGF？）的抑制有关通过增加PI 3 K（磷脂酰肌醇-3-激酶）活性来进行信号传导。因此，我们将测试的假设，相对表达的EVI 1原癌基因及其异常剪接形式有助于卵巢癌的启动，进展和药物反应性，通过不同的影响PI 3 K和TGF？发信号。我们将通过以下三个目标来检验这一假设： 1)我们将确定原癌基因EVI 1异常剪接形式的过表达是否有助于卵巢癌的发生、进展和药物反应。 2)我们将确定EVI 1及其剪接变体是否通过调节PI 3 K和TGF介导不同的细胞效应？信号通路 3)我们将检验EVI 1的剪接变异体预测患者结局的假设。

DESCRIPTION (provided by applicant): Using high resolution comparative genomic hybridization (CGH) array analysis of 235 ovarian cancers, we have narrowed the most frequent region of copy number increase in ovarian cancers to an ~3.2 MB wide region at 3q26.2. Real time PCR of genes within this region indicated that EVI1 (ecotropic viral integration site-1) and an intergenic MDS1/EVI1 fusion transcript were the most highly amplified transcripts within this region. Moreover, EVI1 is aberrantly spliced (Del190-515) in >90% of tumors. MDS1/EVI1 and EVI1 alter proliferation, motility, senescence, and signaling in ovarian epithelial cells. Further, increases in MDS1/EVI1 levels are associated with a good prognosis while EVI1Del190-515 was associated with a poor outcome. Thus, our data suggest that EVI1, MDS1/EVI1, and its splice forms play distinct roles during tumor initiation and progression depending on the cellular context. Patient outcome is likely dependent on the relative levels of the EVI1 splice variants. EVI1 has recently been implicated in cell survival and inhibition of transforming growth factor (TGF beta, TGF?) signaling by increasing PI3K (phosphatidylinositol-3-kinase) activity. Thus, we will test the hypothesis that the relative expression of the EVI1 proto-oncogene and its aberrantly spliced forms contributes to ovarian cancer initiation, progression, and drug responsiveness through differential effects on PI3K and TGF? signaling. We will test this hypothesis through the following three aims: 1) We will determine whether overexpression of aberrantly spliced forms of the proto-oncogene EVI1 contributes to ovarian cancer initiation, progression, and drug responsiveness. 2) We will determine whether EVI1 and its splice variants mediate different cellular effects through regulating the PI3K and TGF? signaling pathways. 3) We will test the hypothesis that splice variants of EVI1 predicts patient outcomes.