title: Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer.
abstract: Physiological levels of Kras(G12D) are sufficient to induce pancreatic intraepithelial neoplasias (PanINs); the mechanisms that drive PanIN progression are unknown. Here, we establish that, in addition to oncogenic Kras(G12D), IL-6 transsignaling-dependent activation of Stat3/Socs3 is required to promote PanIN progression and pancreatic ductal adenocarcinoma (PDAC). Myeloid compartment induces Stat3 activation by secreting IL-6; consequently, IL-6 transsignaling activates Stat3 in the pancreas. Using genetic tools, we show that inactivation of IL-6 transsignaling or Stat3 inhibits PanIN progression and reduces the development of PDAC. Aberrant activation of Stat3 through homozygous deletion of Socs3 in the pancreas accelerates PanIN progression and PDAC development. Our data describe the involvement of IL-6 transsignaling/Stat3/Socs3 in PanIN progression and PDAC development.
authors.affiliation: II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Lesina
authors.forename: Magdalena U
authors.initials: MU
authors.lastname: Kurkowski
authors.forename: Katharina
authors.initials: K
authors.lastname: Ludes
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Matthias
authors.initials: M
authors.lastname: Treiber
authors.forename: Günter
authors.initials: G
authors.lastname: Klöppel
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Reindl
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
authors.forename: Hana
authors.initials: H
authors.lastname: Algül
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000209:etiology*; D018450:Disease Progression; D005260:Female; D011905:Genes, ras; D006801:Humans; D015850:Interleukin-6 / Q000097:blood / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000209:etiology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000502:physiology*
chemical_list: D015850:Interleukin-6; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)