Faculty Collaboration Database

IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation. J Clin Invest 2014 Nov;124(11):4709-22

Date

09/25/2014

Pubmed ID

25250570

Pubmed Central ID

PMC4347237

DOI

10.1172/JCI76037

Scopus ID

2-s2.0-84908609029 (requires institutional sign-in at Scopus site)   38 Citations

Abstract

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.

Author List

Garcia MN, Grasso D, Lopez-Millan MB, Hamidi T, Loncle C, Tomasini R, Lomberk G, Porteu F, Urrutia R, Iovanna JL

Authors

Gwen Lomberk PhD Professor in the Surgery department at Medical College of Wisconsin
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Carcinogenesis
Carcinoma in Situ
Carcinoma, Pancreatic Ductal
Cell Line, Tumor
Extracellular Signal-Regulated MAP Kinases
Humans
Immediate-Early Proteins
MAP Kinase Signaling System
Male
Mice, Nude
Mice, Transgenic
Mutation, Missense
Neoplasm Transplantation
Pancreas
Pancreatic Neoplasms
Phosphorylation
Protein Phosphatase 2
Protein Processing, Post-Translational
Proto-Oncogene Proteins p21(ras)