title: IL17 Functions through the Novel REG3β-JAK2-STAT3 Inflammatory Pathway to Promote the Transition from Chronic Pancreatitis to Pancreatic Cancer.
abstract: Pancreatic ductal adenocarcinoma (PDAC) offers an optimal model for discovering "druggable" molecular pathways that participate in inflammation-associated cancer development. Chronic pancreatitis, a common prolonged inflammatory disease, behaves as a well-known premalignant condition that contributes to PDAC development. Although the mechanisms underlying the pancreatitis-to-cancer transition remain to be fully elucidated, emerging evidence supports the hypothesis that the actions of proinflammatory mediators on cells harboring Kras mutations promote neoplastic transformation. Recent elegant studies demonstrated that the IL17 pathway mediates this phenomenon and can be targeted with antibodies, but the downstream mechanisms by which IL17 functions during this transition are currently unclear. In this study, we demonstrate that IL17 induces the expression of REG3β, a well-known mediator of pancreatitis, during acinar-to-ductal metaplasia and in early pancreatic intraepithelial neoplasia (PanIN) lesions. Furthermore, we found that REG3β promotes cell growth and decreases sensitivity to cell death through activation of the gp130-JAK2-STAT3-dependent pathway. Genetic inactivation of REG3β in the context of oncogenic Kras-driven PDAC resulted in reduced PanIN formation, an effect that could be rescued by administration of exogenous REG3β. Taken together, our findings provide mechanistic insight into the pathways underlying inflammation-associated pancreatic cancer, revealing a dual and contextual pathophysiologic role for REG3β during pancreatitis and PDAC initiation.
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Loncle
authors.affiliation: Experimental Pathology Department, IIBB-CSIC-IDIBAPS, Barcelona, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Bonjoch
authors.affiliation: Experimental Pathology Department, IIBB-CSIC-IDIBAPS, Barcelona, Spain.
authors.forename: Emma
authors.initials: E
authors.lastname: Folch-Puy
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France.
authors.forename: Maria Belen
authors.initials: MB
authors.lastname: Lopez-Millan
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lac
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France.
authors.forename: Maria Inés
authors.initials: MI
authors.lastname: Molejon
authors.affiliation: Laboratory of Immunomodulators, School of Medicine, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET)-University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Chuluyan
authors.affiliation: INSERM UMR U1037, Centre de Recherche sur le Cancer de Toulouse, CHU Rangueil, Toulouse, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Cordelier
authors.affiliation: EA2406, Histologie et pathologie moléculaire des tumeurs, Université de Bordeaux, Bordeaux, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Dubus
authors.affiliation: Laboratory of Epigenetics and Chromatin Dynamics, Gastroenterology Research Unit, Departments of Biochemistry and Molecular Biology, Biophysics, and Medicine, Mayo Clinic, Rochester, New York.
authors.forename: Gwen
authors.initials: G
authors.lastname: Lomberk
authors.affiliation: Laboratory of Epigenetics and Chromatin Dynamics, Gastroenterology Research Unit, Departments of Biochemistry and Molecular Biology, Biophysics, and Medicine, Mayo Clinic, Rochester, New York.
authors.forename: Raul
authors.initials: R
authors.lastname: Urrutia
authors.affiliation: Experimental Pathology Department, IIBB-CSIC-IDIBAPS, Barcelona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Closa
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France. juan.iovanna@inserm.fr.
authors.forename: Juan L
authors.initials: JL
authors.lastname: Iovanna
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D018450:Disease Progression; D006801:Humans; D015151:Immunoblotting; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D020381:Interleukin-17 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D037181:Lectins, C-Type; D051379:Mice; D018345:Mice, Knockout; D010190:Pancreatic Neoplasms / Q000473:pathology*; D050500:Pancreatitis, Chronic / Q000150:complications / Q000378:metabolism; D000073718:Pancreatitis-Associated Proteins; D011230:Precancerous Conditions / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D020381:Interleukin-17; D037181:Lectins, C-Type; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; C000612141:REG3A protein, human; C490253:Reg3b protein, mouse; D050796:STAT3 Transcription Factor; D053614:Janus Kinase 2