The malignant phenotype in breast cancer is driven by eIF4A1-mediated changes in the translational landscape.
The malignant phenotype in breast cancer is driven by eIF4A1-mediated changes in the translational landscape.
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DOI：
10.1038/cddis.2014.542
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发表时间：
2015-01-22
影响因子：
9
通讯作者：
Le Quesne J
中科院分区：
文献类型：
--
作者：
Modelska A;Turro E;Russell R;Beaton J;Sbarrato T;Spriggs K;Miller J;Gräf S;Provenzano E;Blows F;Pharoah P;Caldas C;Le Quesne J
人mRNA DeXD/H-box解旋酶是普遍存在的分子马达，其是涉及RNA代谢的大多数细胞过程所需的。其中最丰富的是eIF 4A，它是在蛋白质合成的起始阶段所必需的，以解开高度结构化的mRNA区域，否则会阻碍扫描核糖体。蛋白质合成失调与肿瘤发生有关，但对RNA解旋酶功能与实体恶性肿瘤恶性表型之间的详细关系知之甚少。因此，对3000多例乳腺肿瘤进行免疫组化分析，以研究eIF 4A 1、解旋酶调节蛋白eIF 4 B、eIF 4 E和PDCD 4的表达与临床结果之间的关系。我们发现eIF 4A 1、eIF 4 B和eIF 4 E是ER阴性乳腺癌预后不良的独立预测因子，而eIF 4A 1抑制剂PDCD 4与ER阳性乳腺癌预后改善相关。与这些数据一致，在培养的MCF 7细胞中调节eIF 4A 1、eIF 4 B和PCDC 4表达都限制了乳腺癌细胞的生长和循环。通过多核糖体分析确定了MCF 7细胞的eIF 4A 1依赖性翻译组，并显示高度富集了几类致癌基因，包括G蛋白组分、细胞周期蛋白和蛋白激酶，以及具有富含G/C的5′ UTR（有可能形成G-四链体）和3′ UTR（含microRNA靶位点）的mRNA。总体而言，我们的数据表明，mRNA解旋的失调有助于乳腺癌的恶性表型，通过优先翻译的一类基因参与在许多水平的促癌信号。此外，免疫组织化学测试是对抗解旋酶疗法敏感的肿瘤的有希望的生物标志物。
Human mRNA DeXD/H-box helicases are ubiquitous molecular motors that are required for the majority of cellular processes that involve RNA metabolism. One of the most abundant is eIF4A, which is required during the initiation phase of protein synthesis to unwind regions of highly structured mRNA that would otherwise impede the scanning ribosome. Dysregulation of protein synthesis is associated with tumorigenesis, but little is known about the detailed relationships between RNA helicase function and the malignant phenotype in solid malignancies. Therefore, immunohistochemical analysis was performed on over 3000 breast tumors to investigate the relationship among expression of eIF4A1, the helicase-modulating proteins eIF4B, eIF4E and PDCD4, and clinical outcome. We found eIF4A1, eIF4B and eIF4E to be independent predictors of poor outcome in ER-negative disease, while in contrast, the eIF4A1 inhibitor PDCD4 was related to improved outcome in ER-positive breast cancer. Consistent with these data, modulation of eIF4A1, eIF4B and PCDC4 expression in cultured MCF7 cells all restricted breast cancer cell growth and cycling. The eIF4A1-dependent translatome of MCF7 cells was defined by polysome profiling, and was shown to be highly enriched for several classes of oncogenic genes, including G-protein constituents, cyclins and protein kinases, and for mRNAs with G/C-rich 5′UTRs with potential to form G-quadruplexes and with 3′UTRs containing microRNA target sites. Overall, our data show that dysregulation of mRNA unwinding contributes to the malignant phenotype in breast cancer via preferential translation of a class of genes involved in pro-oncogenic signaling at numerous levels. Furthermore, immunohistochemical tests are promising biomarkers for tumors sensitive to anti-helicase therapies.