Neuropilin-2 Is upregulated in lung cancer cells during TGF-ß1-induced epithelial-mesenchymal transition.
Cancer Res
; 73(23): 7111-21, 2013 Dec 01.
Article
en En
| MEDLINE
| ID: mdl-24121493
ABSTRACT
The epithelial-mesenchymal transition (EMT) and its reversal, mesenchymal-epithelial transition (MET), are fundamental processes involved in tumor cell invasion and metastasis. SEMA3F is a secreted semaphorin and tumor suppressor downregulated by TGF-ß1 and ZEB1-induced EMT. Here, we report that neuropilin (NRP)-2, the high-affinity receptor for SEMA3F and a coreceptor for certain growth factors, is upregulated during TGF-ß1-driven EMT in lung cancer cells. Mechanistically, NRP2 upregulation was TßRI dependent and SMAD independent, occurring mainly at a posttranscriptional level involving increased association of mRNA with polyribosomes. Extracellular signal-regulated kinase (ERK) and AKT inhibition blocked NRP2 upregulation, whereas RNA interference-mediated attenuation of ZEB1 reduced steady-state NRP2 levels. In addition, NRP2 attenuation inhibited TGF-ß1-driven morphologic transformation, migration/invasion, ERK activation, growth suppression, and changes in gene expression. In a mouse xenograft model of lung cancer, NRP2 attenuation also inhibited locally invasive features of the tumor and reversed TGF-ß1-mediated growth inhibition. In support of these results, human lung cancer specimens with the highest NRP2 expression were predominantly E-cadherin negative. Furthermore, the presence of NRP2 staining strengthened the association of E-cadherin loss with high-grade tumors. Together, our results demonstrate that NRP2 contributes significantly to TGF-ß1-induced EMT in lung cancer.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Carcinoma de Pulmón de Células no Pequeñas
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Neuropilina-2
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Factor de Crecimiento Transformador beta1
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Transición Epitelial-Mesenquimal
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Neoplasias Pulmonares
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Cancer Res
Año:
2013
Tipo del documento:
Article