title: Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression.
abstract: Chronic pancreatitis is a well-known risk factor for pancreatic ductal adenocarcinoma (PDA) development in humans, and inflammation promotes PDA initiation and progression in mouse models of the disease. However, the mechanistic link between inflammatory damage and PDA initiation is unclear. Using a Kras-driven mouse model of PDA, we establish that the inflammatory mediator Stat3 is a critical component of spontaneous and pancreatitis-accelerated PDA precursor formation and supports cell proliferation, metaplasia-associated inflammation, and MMP7 expression during neoplastic development. Furthermore, we show that Stat3 signaling enforces MMP7 expression in PDA cells and that MMP7 deletion limits tumor size and metastasis in mice. Finally, we demonstrate that serum MMP7 level in human patients with PDA correlated with metastatic disease and survival.
authors.affiliation: Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Fukuda
authors.forename: Sam C
authors.initials: SC
authors.lastname: Wang
authors.forename: John P
authors.initials: JP
authors.lastname: Morris
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Folias
authors.forename: Angela
authors.initials: A
authors.lastname: Liou
authors.forename: Grace E
authors.initials: GE
authors.lastname: Kim
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Boucher
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Firpo
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Mulvihill
authors.forename: Matthias
authors.initials: M
authors.lastname: Hebrok
mesh_terms: D000208:Acute Disease; D000230:Adenocarcinoma / Q000209:etiology* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000209:etiology* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D011905:Genes, ras; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000097:blood / Q000502:physiology*; D051379:Mice; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000209:etiology* / Q000473:pathology; D010195:Pancreatitis / Q000150:complications / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000502:physiology*
chemical_list: D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D020783:Matrix Metalloproteinase 7; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)