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

Autores
Loncle, Celine; Bonjoch, Laia; Folch Puy, Emma; Lopez Millan, Maria Belen; Lac, Sophie; Molejon, Maria Ines; Chuluyan, Hector Eduardo; Cordelier, Pierre; Dubus, Pierre; Lomberk, Gwen; Urrutia, Raul; Closa, Daniel; Iovanna, Juan Lucio
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Loncle, Celine. Centre de Recherche en Cancerologie de Marseille; Francia
Fil: Bonjoch, Laia. Instituto de Investigación Biomédica de Barcelona.; España
Fil: Folch Puy, Emma. Instituto de Investigación Biomédica de Barcelona.; España
Fil: Lopez Millan, Maria Belen. Centre de Recherche en Cancerologie de Marseille; Francia
Fil: Lac, Sophie. Centre de Recherche en Cancerologie de Marseille; Francia
Fil: Molejon, Maria Ines. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Centre de Recherche en Cancerologie de Marseille; Francia
Fil: Chuluyan, Hector Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina. Centre de Recherche en Cancerologie de Marseille; Francia
Fil: Cordelier, Pierre. Centre de Recherche sur le Cancer de Toulouse; Francia
Fil: Dubus, Pierre. Université de Bordeaux; Francia
Fil: Lomberk, Gwen. Mayo Clinic Cancer Center; Estados Unidos
Fil: Urrutia, Raul. Mayo Clinic Cancer Center; Estados Unidos
Fil: Closa, Daniel. Instituto de Investigación Biomédica de Barcelona.; España
Fil: Iovanna, Juan Lucio. Centre de Recherche en Cancerologie de Marseille; Francia
Materia
Reg3B
IL17
PANIN
PDAC
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/182688
Acceder
id CONICETDig_0732b03dfcd323a232db8b5b6141b3c8
oai_identifier_str oai:ri.conicet.gov.ar:11336/182688
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling IL17 functions through the novel REG3β-JAK2-STAT3 inflammatory pathway to promote the transition from chronic pancreatitis to pancreatic cancerLoncle, CelineBonjoch, LaiaFolch Puy, EmmaLopez Millan, Maria BelenLac, SophieMolejon, Maria InesChuluyan, Hector EduardoCordelier, PierreDubus, PierreLomberk, GwenUrrutia, RaulClosa, DanielIovanna, Juan LucioReg3BIL17PANINPDAChttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3Pancreatic 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.Fil: Loncle, Celine. Centre de Recherche en Cancerologie de Marseille; FranciaFil: Bonjoch, Laia. Instituto de Investigación Biomédica de Barcelona.; EspañaFil: Folch Puy, Emma. Instituto de Investigación Biomédica de Barcelona.; EspañaFil: Lopez Millan, Maria Belen. Centre de Recherche en Cancerologie de Marseille; FranciaFil: Lac, Sophie. Centre de Recherche en Cancerologie de Marseille; FranciaFil: Molejon, Maria Ines. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Centre de Recherche en Cancerologie de Marseille; FranciaFil: Chuluyan, Hector Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina. Centre de Recherche en Cancerologie de Marseille; FranciaFil: Cordelier, Pierre. Centre de Recherche sur le Cancer de Toulouse; FranciaFil: Dubus, Pierre. Université de Bordeaux; FranciaFil: Lomberk, Gwen. Mayo Clinic Cancer Center; Estados UnidosFil: Urrutia, Raul. Mayo Clinic Cancer Center; Estados UnidosFil: Closa, Daniel. Instituto de Investigación Biomédica de Barcelona.; EspañaFil: Iovanna, Juan Lucio. Centre de Recherche en Cancerologie de Marseille; FranciaAmerican Association for Cancer Research2015-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/182688Loncle, Celine; Bonjoch, Laia; Folch Puy, Emma; Lopez Millan, Maria Belen; Lac, Sophie; et al.; IL17 functions through the novel REG3β-JAK2-STAT3 inflammatory pathway to promote the transition from chronic pancreatitis to pancreatic cancer; American Association for Cancer Research; Cancer Research; 75; 22; 11-2015; 4852-48620008-54721538-7445CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://aacrjournals.org/cancerres/article/75/22/4852/662239/IL17-Functions-through-the-Novel-REG3-JAK2-STAT3info:eu-repo/semantics/altIdentifier/doi/10.1158/0008-5472.CAN-15-0896info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:13:03Zoai:ri.conicet.gov.ar:11336/182688instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 11:13:03.387CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv IL17 functions through the novel REG3β-JAK2-STAT3 inflammatory pathway to promote the transition from chronic pancreatitis to pancreatic cancer
title IL17 functions through the novel REG3β-JAK2-STAT3 inflammatory pathway to promote the transition from chronic pancreatitis to pancreatic cancer
spellingShingle IL17 functions through the novel REG3β-JAK2-STAT3 inflammatory pathway to promote the transition from chronic pancreatitis to pancreatic cancer
Loncle, Celine
Reg3B
IL17
PANIN
PDAC
title_short IL17 functions through the novel REG3β-JAK2-STAT3 inflammatory pathway to promote the transition from chronic pancreatitis to pancreatic cancer
title_full IL17 functions through the novel REG3β-JAK2-STAT3 inflammatory pathway to promote the transition from chronic pancreatitis to pancreatic cancer
title_fullStr IL17 functions through the novel REG3β-JAK2-STAT3 inflammatory pathway to promote the transition from chronic pancreatitis to pancreatic cancer
title_full_unstemmed IL17 functions through the novel REG3β-JAK2-STAT3 inflammatory pathway to promote the transition from chronic pancreatitis to pancreatic cancer
title_sort IL17 functions through the novel REG3β-JAK2-STAT3 inflammatory pathway to promote the transition from chronic pancreatitis to pancreatic cancer
dc.creator.none.fl_str_mv Loncle, Celine
Bonjoch, Laia
Folch Puy, Emma
Lopez Millan, Maria Belen
Lac, Sophie
Molejon, Maria Ines
Chuluyan, Hector Eduardo
Cordelier, Pierre
Dubus, Pierre
Lomberk, Gwen
Urrutia, Raul
Closa, Daniel
Iovanna, Juan Lucio
author Loncle, Celine
author_facet Loncle, Celine
Bonjoch, Laia
Folch Puy, Emma
Lopez Millan, Maria Belen
Lac, Sophie
Molejon, Maria Ines
Chuluyan, Hector Eduardo
Cordelier, Pierre
Dubus, Pierre
Lomberk, Gwen
Urrutia, Raul
Closa, Daniel
Iovanna, Juan Lucio
author_role author
author2 Bonjoch, Laia
Folch Puy, Emma
Lopez Millan, Maria Belen
Lac, Sophie
Molejon, Maria Ines
Chuluyan, Hector Eduardo
Cordelier, Pierre
Dubus, Pierre
Lomberk, Gwen
Urrutia, Raul
Closa, Daniel
Iovanna, Juan Lucio
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Reg3B
IL17
PANIN
PDAC
topic Reg3B
IL17
PANIN
PDAC
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv 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.
Fil: Loncle, Celine. Centre de Recherche en Cancerologie de Marseille; Francia
Fil: Bonjoch, Laia. Instituto de Investigación Biomédica de Barcelona.; España
Fil: Folch Puy, Emma. Instituto de Investigación Biomédica de Barcelona.; España
Fil: Lopez Millan, Maria Belen. Centre de Recherche en Cancerologie de Marseille; Francia
Fil: Lac, Sophie. Centre de Recherche en Cancerologie de Marseille; Francia
Fil: Molejon, Maria Ines. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Centre de Recherche en Cancerologie de Marseille; Francia
Fil: Chuluyan, Hector Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina. Centre de Recherche en Cancerologie de Marseille; Francia
Fil: Cordelier, Pierre. Centre de Recherche sur le Cancer de Toulouse; Francia
Fil: Dubus, Pierre. Université de Bordeaux; Francia
Fil: Lomberk, Gwen. Mayo Clinic Cancer Center; Estados Unidos
Fil: Urrutia, Raul. Mayo Clinic Cancer Center; Estados Unidos
Fil: Closa, Daniel. Instituto de Investigación Biomédica de Barcelona.; España
Fil: Iovanna, Juan Lucio. Centre de Recherche en Cancerologie de Marseille; Francia
description 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.
publishDate 2015
dc.date.none.fl_str_mv 2015-11
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/182688
Loncle, Celine; Bonjoch, Laia; Folch Puy, Emma; Lopez Millan, Maria Belen; Lac, Sophie; et al.; IL17 functions through the novel REG3β-JAK2-STAT3 inflammatory pathway to promote the transition from chronic pancreatitis to pancreatic cancer; American Association for Cancer Research; Cancer Research; 75; 22; 11-2015; 4852-4862
0008-5472
1538-7445
CONICET Digital
CONICET
url http://hdl.handle.net/11336/182688
identifier_str_mv Loncle, Celine; Bonjoch, Laia; Folch Puy, Emma; Lopez Millan, Maria Belen; Lac, Sophie; et al.; IL17 functions through the novel REG3β-JAK2-STAT3 inflammatory pathway to promote the transition from chronic pancreatitis to pancreatic cancer; American Association for Cancer Research; Cancer Research; 75; 22; 11-2015; 4852-4862
0008-5472
1538-7445
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://aacrjournals.org/cancerres/article/75/22/4852/662239/IL17-Functions-through-the-Novel-REG3-JAK2-STAT3
info:eu-repo/semantics/altIdentifier/doi/10.1158/0008-5472.CAN-15-0896
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Association for Cancer Research
publisher.none.fl_str_mv American Association for Cancer Research
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.982451

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