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IL17 Functions through the Novel REG3β-JAK2-STAT3 Inflammatory Pathway to Promote the Transition from Chronic Pancreatitis to Pancreatic Cancer. Cancer Res 2015 Nov 15;75(22):4852-62 PMID: 26404002 PMCID: PMC4651828

Pubmed ID

26404002

DOI

10.1158/0008-5472.CAN-15-0896

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.

Author List

Loncle C, Bonjoch L, Folch-Puy E, Lopez-Millan MB, Lac S, Molejon MI, Chuluyan E, Cordelier P, Dubus P, Lomberk G, Urrutia R, Closa D, Iovanna JL

Authors

Gwen Lomberk PhD Associate 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




Scopus

2-s2.0-84955115797   29 Citations

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

Animals
Antigens, Neoplasm
Biomarkers, Tumor
Carcinoma, Pancreatic Ductal
Cell Line, Tumor
Cell Transformation, Neoplastic
Disease Progression
Humans
Immunoblotting
Inflammation
Interleukin-17
Janus Kinase 2
Lectins, C-Type
Mice
Mice, Knockout
Pancreatic Neoplasms
Pancreatitis, Chronic
Pancreatitis-Associated Proteins
Precancerous Conditions
Proteins
Reverse Transcriptase Polymerase Chain Reaction
STAT3 Transcription Factor
Signal Transduction
jenkins-FCD Prod-310 bff9d975ec7f2d302586822146c2801dd4449aad