Department of Gene Function and Regulation, Institute of Life Sciences Nalco Square, Bhubaneswar, Odisha, India.
Department of Veterinary Pathology, College of Veterinary & Animal Sciences, Wayanad, Kerala, India.
Cell Death Dis. 2018 Jan 16;9(2):18. doi: 10.1038/s41419-017-0036-1.
The most indecipherable component of solid cancer is the development of metastasis which accounts for more than 90% of cancer-related mortalities. A developmental program termed epithelial-mesenchymal transition (EMT) has also been shown to play a critical role in promoting metastasis in epithelium-derived solid tumors. By analyzing publicly available microarray datasets, we observed that ecotropic viral integration site 1 (EVI1) correlates negatively with SLUG, a master regulator of EMT. This correlation was found to be relevant as we demonstrated that EVI1 binds to SLUG promoter element directly through the distal set of zinc fingers and downregulates its expression. Many studies have shown that the primary role of SLUG during EMT and EMT-like processes is the regulation of cell motility in most of the cancer cells. Knockdown of EVI1 in metastatic colon cancer cell and subsequent passage through matrigel not only increased the invading capacity but also induced an EMT-like morphological feature of the cells, such as spindle-shaped appearance and led to a significant reduction in the expression of the epithelial marker, E-CADHERIN and increase in the expression of the mesenchymal marker, N-CADHERIN. The cells, when injected into immunocompromised mice, failed to show any metastatic foci in distant organs however the ones with EVI1, metastasized in the intraperitoneal layer and also showed multiple micro metastatic foci in the lungs and spleen. These findings suggest that in colon cancer EVI1 is dispensable for epithelial-mesenchymal transition, however, is required for metastasis.
实体瘤中最难以捉摸的部分是转移的发展，转移占癌症相关死亡的 90%以上。一个被称为上皮-间充质转化（EMT）的发育程序也被证明在促进上皮源性实体瘤转移中起着关键作用。通过分析公开的微阵列数据集，我们观察到，嗜性病毒整合位点 1（EVI1）与 EMT 的主调控因子 SLUG 呈负相关。这种相关性是相关的，因为我们证明 EVI1 通过远端锌指直接结合到 SLUG 启动子元件并下调其表达。许多研究表明，在 EMT 和 EMT 样过程中，SLUG 的主要作用是调节大多数癌细胞的细胞迁移能力。在转移性结肠癌细胞中敲低 EVI1，随后通过基质胶进行传代，不仅增加了侵袭能力，而且诱导细胞出现 EMT 样形态特征，如纺锤形外观，并导致上皮标志物 E-钙黏蛋白的表达显著减少，间充质标志物 N-钙黏蛋白的表达增加。当这些细胞被注射到免疫缺陷小鼠中时，在远处器官中没有显示出任何转移灶，但那些有 EVI1 的细胞在腹膜层转移，并在肺部和脾脏中显示出多个微转移灶。这些发现表明，在结肠癌中，EVI1 对于上皮-间充质转化不是必需的，但对于转移是必需的。
