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Cancer Lett ; 505: 75-86, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33609609

RESUMO

In many tumors, CD73 (NT5E), a rate-limiting enzyme in adenosine biosynthesis, is upregulated by TGF-ß and drives tumor progression. Conversely, CD73 is downregulated in endometrial carcinomas (EC) despite a TGF-ß-rich environment. Through gene expression analyses of normal endometrium samples of the uterine cancer TCGA data set and genetic and pharmacological studies, we discovered CD73 loss shifts TGF-ß1 from tumor suppressor to promoter in EC. TGF-ß1 upregulated CD73 and epithelial integrity in vivo in the normal endometrium and in vitro in early stage EC cells. With loss of CD73, TGF-ß1-mediated epithelial integrity was abrogated. EC cells developed TGF-ß1-mediated stress fibers and macromolecule permeability, migration, and invasion increased. In human tumors, CD73 is downregulated in deeply invasive stage I EC. Consistent with shifting TGF-ß1 activity, CD73 loss increased TGF-ß1-mediated canonical signaling and upregulated cyclin D1 (CCND1) and downregulated p21 expression. This shift was clinically relevant, as CD73Low/CCND1High expression associated with poor tumor differentiation, increased myometrial and lymphatic/vascular space invasion, and patient death. Further loss of CD73 in CD73Low expressing advanced stage EC cells increased TGF-ß-mediated stress fibers, signaling, and invasiveness, whereby adenosine A1 receptor agonist, CPA, dampened TGF-ß-mediated invasion. These data identify CD73 loss as essential for shifting TGF-ß activity in EC.


Assuntos
5'-Nucleotidase/fisiologia , Neoplasias do Endométrio/patologia , Fator de Crescimento Transformador beta1/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Adenosina/fisiologia , Adulto , Idoso , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Feminino , Proteínas Ligadas por GPI/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Estadiamento de Neoplasias
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