Insulin-Like Growth Factor 2 mRNA-Binding Protein 3 is a Novel Post-Transcriptional Regulator of Ewing Sarcoma Malignancy
Insulin-Like Growth Factor 2 mRNA-Binding Protein 3 is a Novel Post-Transcriptional Regulator of Ewing Sarcoma Malignancy
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DOI：
10.1158/1078-0432.ccr-17-2602
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发表时间：
2018-08-01
影响因子：
11.5
通讯作者：
Scotlandi, Katia
中科院分区：
文献类型：
--
作者：
Mancarella, Caterina;Pasello, Michela;Scotlandi, Katia
目的：大规模测序研究表明，除基因组改变外，基因表达的转录后调控或表观遗传机制在很大程度上影响尤文肉瘤的临床行为。我们研究了RNA结合蛋白IGF2BP3在调节尤文肉瘤侵袭性中的意义。实验设计：采用RNA测序技术对14例局限性尤文肉瘤患者进行探索性研究。接下来，128例局限性尤文肉瘤患者被分成两个队列。在训练集中，使用Affymetrix基因芯片阵列分析了29个尤文肉瘤样本。在验证集中，99个尤文肉瘤样本用qRT-PCR进行了检测。结果：单变量和多变量分析显示IGF2BP3是预后不良的有力指标。此外，ABCF1mRNA被鉴定为IGF2BP3的一个新的伙伴。功能研究表明，IGF2BP3是致癌驱动因子，ABCF1mRNA是通过结合IGF2BP3而部分抑制其功能的海绵。IGF2BP3和ABCF1的联合评估可以识别不同的患者结局--高IGF2BP3和低ABCF1水平意味着较差的存活率(25%)，而低IGF2BP3和高ABCF1水平意味着较好的存活率(85.5%)。溴域和端外域抑制剂JQ1降低IGF2BP3的表达，改变其有效靶点的表达，并抑制尤文肉瘤细胞在锚定非依赖条件下的生长能力。结论：联合检测IGF2BP3和ABCF1可预测尤文肉瘤患者的复发。因此，对于IGF2BP3高表达和生存概率较低的患者，应临床评估BETIS的使用情况。(C)2018年AACR。
Purpose: Large-scale sequencing studies have indicated that besides genomic alterations, the posttranscriptional regulation of gene expression or epigenetic mechanisms largely influences the clinical behavior of Ewing sarcoma. We investigated the significance of the RNA-binding protein IGF2BP3 in the regulation of Ewing sarcoma aggressiveness.Experimental Design: Explorative study was performed in 14 patients with localized Ewing sarcoma using RNA sequencing. Next, 128 patients with localized Ewing sarcoma were divided into two cohorts. In the training set, 29 Ewing sarcoma samples were analyzed using Affymetrix GeneChip arrays. In the validation set, 99 Ewing sarcoma samples were examined using qRT-PCR. Patient-derived cell lines and experimental models were used for functional studies.Results: Univariate and multivariate analyses indicated IGF2BP3 as a potent indicator of poor prognosis. Furthermore, ABCF1 mRNA was identified as a novel partner of IGF2BP3. Functional studies indicated IGF2BP3 as an oncogenic driver and ABCF1 mRNA as a sponge that by binding IGF2BP3, partly repressed its functions. The combined evaluation of IGF2BP3 and ABCF1 could identify different patient outcomes-high IGF2BP3 and low ABCF1 levels indicated poor survival (25%), whereas low IGF2BP3 and high ABCF1 levels indicated favorable survival (85.5%). The bromodomain and extraterminal domain inhibitor (BETi) JQ1 decreased IGF2BP3 expression, modified the expression of its validated targets and inhibited the capability of Ewing sarcoma cells to grow under anchorage-independent conditions.Conclusions: The combined assessment of IGF2BP3 and ABCF1 predicts recurrence in Ewing sarcoma patients. Thus, for patients with high expression of IGF2BP3 and poor probability of survival, the use of BETis should be clinically evaluated. (C) 2018 AACR.