Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
J Clin Invest. 2011 Apr;121(4):1373-85. doi: 10.1172/JCI42579. Epub 2011 Mar 14.
Epithelial tumor cells transit to a mesenchymal state in response to extracellular cues, in a process known as epithelial-to-mesenchymal transition (EMT). The precise nature of these cues has not been fully defined, an important issue given that EMT is an early event in tumor metastasis. Here, we have found that a population of metastasis-prone mouse lung adenocarcinoma cells expresses Notch and Notch ligands and that the Notch ligand Jagged2 promotes metastasis. Mechanistically, Jagged2 was found to promote metastasis by increasing the expression of GATA-binding (Gata) factors, which suppressed expression of the microRNA-200 (miR-200) family of microRNAs that target the transcriptional repressors that drive EMT and thereby induced EMT. Reciprocally, miR-200 inhibited expression of Gata3, which reversed EMT and abrogated metastasis, suggesting that Gata3 and miR-200 are mutually inhibitory and have opposing effects on EMT and metastasis. Consistent with this, high levels of Gata3 expression correlated with EMT in primary tumors from 2 cohorts of lung adenocarcinoma patients. These findings reveal what we believe to be a novel Jagged2/miR-200-dependent pathway that mediates lung adenocarcinoma EMT and metastasis in mice and may have implications for the treatment of human epithelial tumors.
上皮肿瘤细胞在受到细胞外信号刺激时会发生上皮-间质转化（EMT），从上皮细胞表型转变成间充质细胞表型。这些信号的精确性质尚未完全确定，这是一个重要的问题，因为 EMT 是肿瘤转移的早期事件。在这里，我们发现一群易转移的小鼠肺腺癌细胞表达 Notch 和 Notch 配体，并且 Notch 配体 Jagged2 促进转移。从机制上讲，Jagged2 通过增加 GATA 结合（Gata）因子的表达来促进转移，Gata 因子抑制了驱动 EMT 的转录抑制因子的表达，从而诱导 EMT。反过来，miR-200 抑制了 Gata3 的表达，逆转了 EMT 并阻断了转移，这表明 Gata3 和 miR-200 是相互抑制的，对 EMT 和转移有相反的影响。与此一致的是，来自两个肺腺癌患者队列的原发性肿瘤中高水平的 Gata3 表达与 EMT 相关。这些发现揭示了我们认为的一种新的 Jagged2/miR-200 依赖途径，该途径介导了小鼠肺腺癌的 EMT 和转移，可能对人类上皮肿瘤的治疗具有意义。
