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Artículo

IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation

Garcia, Maria NoeIcon ; Grasso, Daniel HectorIcon ; Lopez Millian, Maria Belen; Hamidi, Tewfik; Loncle, Celine; Tomasini, Richard; Lomberk, Gwen; Porteu, Françoise; Urrutia, Raul; Iovanna, Juan Lucio
Fecha de publicación: 09/2014
Editorial: American Society for Clinical Investigation
Revista: Journal of Clinical Investigation
ISSN: 0021-9738
e-ISSN: 1558-8238
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Patología

Resumen

Activating mutations in the KRAS oncogene are prevalent in pancreatic ductal adenocarcinoma (PDAC). We previously demonstrated that pancreatic intraepithelial neoplasia (PanIN) formation, which precedes malignant transformation, associates with the expression of immediate early response 3 (Ier3) as part of a prooncogenic transcriptional pathway. Here, we evaluated the role of IER3 in PanIN formation and PDAC development. In human pancreatic cancer cells, IER3 expression efficiently sustained ERK1/2 phosphorylation by inhibiting phosphatase PP2A activity. Moreover, IER3 enhanced KrasG12D-dependent oncogenesis in the pancreas, as both PanIN and PDAC development were delayed in IER3-deficient KrasG12D mice. IER3 expression was discrete in healthy acinar cells, becoming highly prominent in peritumoral acini, and particularly high in acinar ductal metaplasia (ADM) and PanIN lesions, where IER3 colocalized with phosphorylated ERK1/2. However, IER3 was absent in undifferentiated PDAC, which suggests that the IER3-dependent pathway is an early event in pancreatic tumorigenesis. IER3 expression was induced by both mild and severe pancreatitis, which promoted PanIN formation and progression to PDAC in KrasG12D mice. In IER3-deficient mice, pancreatitis abolished KrasG12D-induced proliferation, which suggests that pancreatitis enhances the oncogenic effect of KRAS through induction of IER3 expression. Together, our data indicate that IER3 supports KRASG12D-associated oncogenesis in the pancreas by sustaining ERK1/2 phosphorylation via phosphatase PP2A inhibition.
Palabras clave: Pancreatic Cancer , Ier3
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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution 2.5 Unported (CC BY 2.5)
Identificadores
URI: http://hdl.handle.net/11336/30777
DOI: http://dx.doi.org/10.1172/JCI76037
URL: https://www.jci.org/articles/view/76037
Colecciones
Articulos(IBIMOL)
Articulos de INSTITUTO DE BIOQUIMICA Y MEDICINA MOLECULAR
Citación
Garcia, Maria Noe; Grasso, Daniel Hector; Lopez Millian, Maria Belen; Hamidi, Tewfik; Loncle, Celine; et al.; IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation; American Society for Clinical Investigation; Journal of Clinical Investigation; 124; 11; 9-2014; 4709-4722; 76037
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