Intratumoral bidirectional transitions between epithelial and mesenchymal cells in triple-negative breast cancer.
Intratumoral bidirectional transitions between epithelial and mesenchymal cells in triple-negative breast cancer.
复制标题
DOI：
10.1111/cas.13246
复制
发表时间：
2017-06
期刊：
影响因子：
5.7
通讯作者：
Inoue JI
中科院分区：
文献类型：
--
作者：
Yamamoto M;Sakane K;Tominaga K;Gotoh N;Niwa T;Kikuchi Y;Tada K;Goshima N;Semba K;Inoue JI
上皮-间质转化（Epithelial-mesenchymal transition，EMT）及其逆转过程间质-上皮转化MET（mesenchymal-epithelial transition，MET）是肿瘤转移的重要环节。然而，由于EMT和MET过程是动态的，间充质癌细胞可能短暂地经历MET，随后重新经历EMT以重新开始转移过程。因此，转移过程中EMT和MET之间可能存在时空协调的相互调节。为了阐明这种调控，我们选择了人类三阴性乳腺癌细胞系HCC 38，因为HCC 38由固定比例的上皮细胞和间充质细胞群组成，尽管间充质细胞的增殖速度明显慢于上皮细胞。我们从Venus标记和未标记的HCC 38细胞中纯化上皮细胞和间充质细胞，并将它们以各种比例混合以进行EMT和MET。使用这个系统，我们发现EMT的效率大约比MET高一个数量级，并且这两个群体显着增强了细胞从另一个群体到自己群体的转变。此外，锌指E盒结合同源异型盒1（ZEB 1）或锌指蛋白SNAI 2（SLUG）的敲低显著抑制EMT，但促进部分MET，表明ZEB 1和SLUG对EMT和MET至关重要。我们还表明，原发性乳腺癌细胞经历EMT，与决定EMT状态和乳腺癌亚型的基因表达谱的变化相关。这些变化与HCC 38细胞EMT中观察到的变化非常相似。因此，我们提出HCC 38作为一个合适的模型来分析可能影响三阴性乳腺癌发展的EMT-MET动力学。
Epithelial–mesenchymal transition (EMT) and its reverse process, mesenchymal–epithelial transition MET, are crucial in several stages of cancer metastasis. Epithelial–mesenchymal transition allows cancer cells to move to proximal blood vessels for intravasation. However, because EMT and MET processes are dynamic, mesenchymal cancer cells are likely to undergo MET transiently and subsequently re‐undergo EMT to restart the metastatic process. Therefore, spatiotemporally coordinated mutual regulation between EMT and MET could occur during metastasis. To elucidate such regulation, we chose HCC38, a human triple‐negative breast cancer cell line, because HCC38 is composed of epithelial and mesenchymal populations at a fixed ratio even though mesenchymal cells proliferate significantly more slowly than epithelial cells. We purified epithelial and mesenchymal cells from Venus‐labeled and unlabeled HCC38 cells and mixed them at various ratios to follow EMT and MET. Using this system, we found that the efficiency of EMT is approximately an order of magnitude higher than that of MET and that the two populations significantly enhance the transition of cells from the other population to their own. In addition, knockdown of Zinc finger E‐box‐binding homeobox 1 (ZEB1) or Zinc finger protein SNAI2 (SLUG) significantly suppressed EMT but promoted partial MET, indicating that ZEB1 and SLUG are crucial to EMT and MET. We also show that primary breast cancer cells underwent EMT that correlated with changes in expression profiles of genes determining EMT status and breast cancer subtype. These changes were very similar to those observed in EMT in HCC38 cells. Consequently, we propose HCC38 as a suitable model to analyze EMT–MET dynamics that could affect the development of triple‐negative breast cancer.