title: IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylation.
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.
authors.forename: Maria Noé
authors.initials: MN
authors.lastname: Garcia
authors.forename: Daniel
authors.initials: D
authors.lastname: Grasso
authors.forename: Maria Belen
authors.initials: MB
authors.lastname: Lopez-Millan
authors.forename: Tewfik
authors.initials: T
authors.lastname: Hamidi
authors.forename: Celine
authors.initials: C
authors.lastname: Loncle
authors.forename: Richard
authors.initials: R
authors.lastname: Tomasini
authors.forename: Gwen
authors.initials: G
authors.lastname: Lomberk
authors.forename: Françoise
authors.initials: F
authors.lastname: Porteu
authors.forename: Raul
authors.initials: R
authors.lastname: Urrutia
authors.forename: Juan L
authors.initials: JL
authors.lastname: Iovanna
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D002278:Carcinoma in Situ / Q000235:genetics* / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008297:Male; D008819:Mice, Nude; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009368:Neoplasm Transplantation; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*
chemical_list: C518820:IEX-1 protein, mouse; D017874:Immediate-Early Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D054648:Protein Phosphatase 2; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)