IL17 functions through the novel REG3β-JAK2-STAT3 inflammatory pathway to promote the transition from chronic pancreatitis to pancreatic cancer

Celine Loncle, Laia Bonjoch, Emma Folch-Puy, Maria Belen Lopez-Millan, Sophie Lac, Maria Inés Molejon, Eduardo Chuluyan, Pierre Cordelier, Pierre Dubus, Gwen Lomberk, Raul Urrutia, Daniel Closa, Juan L. Iovanna

Research output: Contribution to journalArticle

49 Scopus citations

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 wellknown 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.

Original languageEnglish (US)
Pages (from-to)4852-4862
Number of pages11
JournalCancer research
Volume75
Issue number22
DOIs
StatePublished - Nov 15 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Loncle, C., Bonjoch, L., Folch-Puy, E., Lopez-Millan, M. B., Lac, S., Molejon, M. I., Chuluyan, E., Cordelier, P., Dubus, P., Lomberk, G., Urrutia, R., Closa, D., & Iovanna, J. L. (2015). IL17 functions through the novel REG3β-JAK2-STAT3 inflammatory pathway to promote the transition from chronic pancreatitis to pancreatic cancer. Cancer research, 75(22), 4852-4862. https://doi.org/10.1158/0008-5472.CAN-15-0896