Decreased eIF3e/Int6 expression causes epithelial-to-mesenchymal transition in breast epithelial cells
Decreased eIF3e/Int6 expression causes epithelial-to-mesenchymal transition in breast epithelial cells
复制标题
DOI：
10.1038/onc.2012.371
复制
发表时间：
2013-08-01
期刊：
影响因子：
8
通讯作者：
Lewis, S. M.
中科院分区：
文献类型：
--
作者：
Gillis, L. D.;Lewis, S. M.
EIF3e/Int6是多亚单位eIF3复合体的一个组成部分，它直接与40S核糖体结合，促进核糖体募集到mRNA，从而促进蛋白质的合成。在高达37%的人类乳腺癌中发现eIF3e/Int6表达降低，而小鼠eIF3e/Int6蛋白的截短突变版本的表达会导致正常乳腺细胞的恶性转化。这些发现表明eIF3e/Int6是一种肿瘤抑制基因；然而，最近的一项研究报道，eIF3e/Int6在乳腺癌细胞中的表达减少导致癌基因翻译减少，这表明eIF3e/Int6实际上可能在乳腺癌中具有致癌作用。为了更好地了解eIF3e/Int6在乳腺癌中的作用，我们研究了eIF3e/Int6在永生化乳腺上皮细胞系MCF-10A中表达降低的影响。令人惊讶的是，我们发现eIF3e/Int6的表达减少导致乳腺上皮细胞经历上皮向间充质转化(EMT)。我们发现eIF3e/Int6表达降低所诱导的EMT赋予乳腺上皮细胞侵袭和迁移特性，提示eIF3e/Int6对EMT的调控可能在乳腺癌转移中起重要作用。此外，我们还发现，乳腺上皮细胞中eIF3e/Int6的表达减少会导致关键的EMT调节因子Snail1和ZEB2的表达特异性增加，这种表达在转录和转录后水平上都会发生。总之，我们的数据表明eIF3e/Int6在调节乳腺上皮细胞EMT中发挥了新的作用，并支持eIF3e/Int6的肿瘤抑制作用。
eIF3e/Int6 is a component of the multi-subunit eIF3 complex, which binds directly to the 40S ribosome to facilitate ribosome recruitment to mRNA and hence protein synthesis. Reduced expression of eIF3e/Int6 has been found in up to 37% of human breast cancers, and expression of a truncated mutant version of the mouse eIF3e/Int6 protein leads to malignant transformation of normal mammary cells. These findings suggest that eIF3e/Int6 is a tumor suppressor; however, a recent study has reported that a reduction of eIF3e/Int6 expression in breast cancer cells leads to reduced translation of oncogenes, suggesting that eIF3e/Int6 may in fact have an oncogenic role in breast cancer. To gain a better understanding of the role of eIF3e/Int6 in breast cancer, we have examined the effects of decreased eIF3e/Int6 expression in an immortalized breast epithelial cell line, MCF-10A. Surprisingly, we find that decreased expression of eIF3e/Int6 causes breast epithelial cells to undergo epithelial-to-mesenchymal transition (EMT). We show that EMT induced by a decrease in eIF3e/Int6 expression imparts invasive and migratory properties to breast epithelial cells, suggesting that regulation of EMT by eIF3e/Int6 may have an important role in breast cancer metastasis. Furthermore, we show that reduced eIF3e/Int6 expression in breast epithelial cells causes a specific increase in the expression of the key EMT regulators Snail1 and Zeb2, which occurs at both the transcriptional and post-transcriptional levels. Together, our data indicate a novel role of eIF3e/Int6 in the regulation of EMT in breast epithelial cells and support a tumor suppressor role of eIF3e/Int6.