Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis
| العنوان: | Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis |
|---|---|
| المؤلفون: | Madeleine J. Oudin, Vasilena Gocheva, Charles A. Whittaker, Roderick T. Bronson, Tyler Jacks, Carman Man-Chung Li, Sheng Rong Ng, Shi Yun Wang, Arjun Bhutkar, Eric L. Snyder, Frank B. Gertler, Saya R. Date |
| المساهمون: | Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Mechanical Engineering, Koch Institute for Integrative Cancer Research at MIT, Li, Carman Man-Chung, Gocheva, Vasilena, Oudin, Madeleine Julie, Bhutkar, Arjun (AJ), Wang, Shi Yun, Date, Saya R., Ng, Sheng Rong, Whittaker, Charles A., Gertler, Frank, Jacks, Tyler E. |
| المصدر: | Cold Spring Harbor Laboratory Press |
| بيانات النشر: | Cold Spring Harbor Laboratory Press, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Lung Neoplasms, Thyroid Nuclear Factor 1, Mice, Nude, Adenocarcinoma of Lung, Adenocarcinoma, Proto-Oncogene Mas, Metastasis, Animals, Genetically Modified, Mice, HMGA2, Cell Line, Tumor, Genetics, medicine, Gene silencing, Animals, Humans, CDX2 Transcription Factor, Gene Silencing, Neoplasm Metastasis, CDX2, Lung cancer, Homeodomain Proteins, Gene knockdown, biology, Nuclear Proteins, respiratory system, medicine.disease, digestive system diseases, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Invadopodia, embryonic structures, biology.protein, Cancer research, Hepatocyte Nuclear Factor 3-beta, Developmental Biology, Research Paper, Transcription Factors |
| الوصف: | Despite the fact that the majority of lung cancer deaths are due to metastasis, the molecular mechanisms driving metastatic progression are poorly understood. Here, we present evidence that loss of Foxa2 and Cdx2 synergizes with loss of Nkx2-1 to fully activate the metastatic program. These three lineage-specific transcription factors are consistently down-regulated in metastatic cells compared with nonmetastatic cells. Knockdown of these three factors acts synergistically and is sufficient to promote the metastatic potential of nonmetastatic cells to that of naturally arising metastatic cells in vivo. Furthermore, silencing of these three transcription factors is sufficient to account for a significant fraction of the gene expression differences between the nonmetastatic and metastatic states in lung adenocarcinoma, including up-regulated expression of the invadopodia component Tks5[subscript long], the embryonal proto-oncogene Hmga2, and the epithelial-to-mesenchymal mediator Snail. Finally, analyses of tumors from a genetically engineered mouse model and patients show that low expression of Nkx2-1, Foxa2, and Cdx2 strongly correlates with more advanced tumors and worse survival. Our findings reveal that a large part of the complex transcriptional network in metastasis can be controlled by a small number of regulatory nodes that function redundantly, and loss of multiple nodes is required to fully activate the metastatic program. National Cancer Institute (U.S.) (Cancer Center Support Grant P30-CA14051) Howard Hughes Medical Institute National Institutes of Health (U.S.) (Grant 5-U01-CA84306) United States. Dept. of Defense. Breast Cancer Research Program (U.S.) (Grant W81XWH-12-1-0031) Ludwig Center for Molecular Oncology |
| وصف الملف: | application/pdf |
| اللغة: | English |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::63efd957f50344a664f09ead6318f8d8 https://orcid.org/0000-0003-3214-4554 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....63efd957f50344a664f09ead6318f8d8 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |