Abstract
Metastasis is the leading cause of death in people with lung cancer, yet the molecular effectors underlying tumor dissemination remain poorly defined. Through the development of an in vivo spontaneous lung cancer metastasis model, we show that the developmentally regulated transcriptional repressor Capicua (CIC) suppresses invasion and metastasis. Inactivation of CIC relieves repression of its effector ETV4, driving ETV4-mediated upregulation of MMP24, which is necessary and sufficient for metastasis. Loss of CIC, or an increase in levels of its effectors ETV4 and MMP24, is a biomarker of tumor progression and worse outcomes in people with lung and/or gastric cancer. Our findings reveal CIC as a conserved metastasis suppressor, highlighting new anti-metastatic strategies that could potentially improve patient outcomes.
MeSH terms
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Adenovirus E1A Proteins / genetics
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Adenovirus E1A Proteins / metabolism*
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Animals
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / metabolism
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Carcinoma, Non-Small-Cell Lung / secondary*
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Female
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Gene Expression Profiling
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Humans
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology*
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Matrix Metalloproteinases, Membrane-Associated / genetics
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Matrix Metalloproteinases, Membrane-Associated / metabolism*
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Mice
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Mice, SCID
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-ets
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Repressor Proteins / antagonists & inhibitors*
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Tumor Cells, Cultured
Substances
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Adenovirus E1A Proteins
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CIC protein, human
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Cic protein, mouse
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ETV4 protein, human
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-ets
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Repressor Proteins
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MMP24 protein, human
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Matrix Metalloproteinases, Membrane-Associated