Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
Oncogene. 2010 Jul 15;29(28):4080-9. doi: 10.1038/onc.2010.152. Epub 2010 May 10.
Altered expression of the eukaryotic translation initiation factor 3 (eIF3) subunit eIF3e/INT6 has been described in various types of human cancer, but the nature of its involvement in tumorigenesis is not yet clear. Using immunohistochemical analysis of 81 primary breast cancers, we found that high tumor grade correlated significantly with elevated cytoplasmic eIF3e level in epithelial tumor cells. Analysis of protein synthesis after siRNA-mediated knockdown in breast cancer cell lines indicated that eIF3e is not required for bulk translation. Microarray analysis of total and polysomal RNAs nonetheless identified distinct sets of mRNAs regulated either positively or negatively by eIF3e; functional classification of these revealed a marked enrichment of genes involved in cell proliferation, invasion and apoptosis. Validated mRNA targets regulated positively at the translational level by eIF3e included urokinase-type plasminogen activator and apoptotic regulator BCL-XL, whereas synthesis of proteins including the mitotic checkpoint component MAD2L1 was negatively regulated. Finally, eIF3e-depleted breast carcinoma cells showed reduced in vitro invasion and proliferation. Taken together, our study data suggest that eIF3e has a positive role in breast cancer progression. It regulates the translation, and in some cases abundance, of mRNAs involved in key aspects of cancer cell biology.
真核翻译起始因子 3（eIF3）亚基 eIF3e/INT6 的表达改变已在各种类型的人类癌症中被描述，但它在肿瘤发生中的作用性质尚不清楚。使用 81 例原发性乳腺癌的免疫组织化学分析，我们发现高肿瘤分级与上皮肿瘤细胞中细胞质 eIF3e 水平升高显著相关。在乳腺癌细胞系中通过 siRNA 介导的敲低分析蛋白质合成后，表明 eIF3e 对于批量翻译不是必需的。然而，对总 RNA 和多核糖体 RNA 的微阵列分析确定了由 eIF3e 正向或负向调节的不同的 mRNA 集；对这些基因进行功能分类，发现参与细胞增殖、侵袭和凋亡的基因明显富集。eIF3e 在翻译水平上正向调节的验证的 mRNA 靶标包括尿激酶型纤溶酶原激活物和凋亡调节因子 BCL-XL，而包括有丝分裂检查点成分 MAD2L1 的蛋白质的合成则受到负向调节。最后，eIF3e 耗尽的乳腺癌细胞显示体外侵袭和增殖减少。总之，我们的研究数据表明，eIF3e 在乳腺癌进展中具有积极作用。它调节参与癌细胞生物学关键方面的 mRNA 的翻译，并且在某些情况下调节其丰度。
