期刊
GENES & DEVELOPMENT
卷 23, 期 18, 页码 2140-2151出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.1820209
关键词
Lung cancer; EMT; microRNA-200; mouse model; metastasis
资金
- NIH [5 T32 CA009666, P50 CA70907]
- R01 [CA132608, CA117965]
- David M. Sather Memorial Fund
- The Armour Family Lung Cancer Research Fund
- Dan L. Duncan Cancer Center at Baylor College of Medicine
- The ASCO Cancer Foundation [P50 CA70907, R01 CA129632]
- International Association for the Study of Lung Cancer ( IASLC) Fellow Grant
- [P30 CA125123]
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.
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