Gibbons Don L, Lin Wei, Creighton Chad J, Rizvi Zain H, Gregory Philip A, Goodall Gregory J, Thilaganathan Nishan, Du Liqin, Zhang Yiqun, Pertsemlidis Alexander, Kurie Jonathan M
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Genes Dev. 2009 Sep 15;23(18):2140-51. doi: 10.1101/gad.1820209.
Metastatic disease is a primary cause of cancer-related death, and factors governing tumor cell metastasis have not been fully elucidated. Here, we address this question by using tumor cell lines derived from mice that develop metastatic lung adenocarcinoma owing to expression of mutant K-ras and p53. Despite having widespread somatic genetic alterations, the metastasis-prone tumor cells retained a marked plasticity. They transited reversibly between epithelial and mesenchymal states, forming highly polarized epithelial spheres in three-dimensional culture that underwent epithelial-to-mesenchymal transition (EMT) following treatment with transforming growth factor-beta or injection into syngeneic mice. This transition was entirely dependent on the microRNA (miR)-200 family, which decreased during EMT. Forced expression of miR-200 abrogated the capacity of these tumor cells to undergo EMT, invade, and metastasize, and conferred transcriptional features of metastasis-incompetent tumor cells. We conclude that tumor cell metastasis is regulated by miR-200 expression, which changes in response to contextual extracellular cues.
转移性疾病是癌症相关死亡的主要原因，而控制肿瘤细胞转移的因素尚未完全阐明。在这里，我们通过使用源自小鼠的肿瘤细胞系来解决这个问题，这些小鼠由于突变型K-ras和p53的表达而发生转移性肺腺癌。尽管存在广泛的体细胞基因改变，但易于转移的肿瘤细胞仍具有显著的可塑性。它们在上皮和间充质状态之间可逆地转变，在三维培养中形成高度极化的上皮球，在用转化生长因子-β处理或注射到同基因小鼠后经历上皮-间充质转化（EMT）。这种转变完全依赖于微小RNA（miR）-200家族，其在EMT过程中减少。miR-200的强制表达消除了这些肿瘤细胞进行EMT、侵袭和转移的能力，并赋予了无转移能力的肿瘤细胞的转录特征。我们得出结论，肿瘤细胞转移受miR-200表达的调节，并根据周围的细胞外信号而变化。
