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Cell ; 154(2): 311-324, 2013 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-23830207

RESUMO

Tumor cells metastasize to distant organs through genetic and epigenetic alterations, including changes in microRNA (miR) expression. Here we find miR-22 triggers epithelial-mesenchymal transition (EMT), enhances invasiveness and promotes metastasis in mouse xenografts. In a conditional mammary gland-specific transgenic (TG) mouse model, we show that miR-22 enhances mammary gland side-branching, expands the stem cell compartment, and promotes tumor development. Critically, miR-22 promotes aggressive metastatic disease in MMTV-miR-22 TG mice, as well as compound MMTV-neu or -PyVT-miR-22 TG mice. We demonstrate that miR-22 exerts its metastatic potential by silencing antimetastatic miR-200 through direct targeting of the TET (Ten eleven translocation) family of methylcytosine dioxygenases, thereby inhibiting demethylation of the mir-200 promoter. Finally, we show that miR-22 overexpression correlates with poor clinical outcomes and silencing of the TET-miR-200 axis in patients. Taken together, our findings implicate miR-22 as a crucial epigenetic modifier and promoter of EMT and breast cancer stemness toward metastasis.


Assuntos
Neoplasias da Mama/patologia , Montagem e Desmontagem da Cromatina , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , Metástase Neoplásica , Células-Tronco Neoplásicas/metabolismo , 5-Metilcitosina/análogos & derivados , Animais , Neoplasias da Mama/metabolismo , Citosina/análogos & derivados , Citosina/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Transplante de Neoplasias , Proteínas Proto-Oncogênicas/metabolismo , Interferência de RNA , Transplante Heterólogo
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