title: Activation of the IL-6R/Jak/stat pathway is associated with a poor outcome in resected pancreatic ductal adenocarcinoma.
abstract: OBJECTIVE
  Chronic localized pancreatic inflammation in the form of chronic pancreatitis is an established risk factor for human pancreatic ductal adenocarcinoma (PDAC) development. Constitutive activation of inflammation-related signal transducer and activator of transcription (Stat)3 signaling has been implicated in the development and progression a number of malignancies, including PDAC. Although, the Janus Kinase (Jak)/Stat pathway is a potential drug target, clinicopathological, molecular, and prognostic features of Stat3-activated PDAC remain uncertain. Our aim was to determine the clinicopathological impact of this inflammatory pathway in resectable PDAC.
  
  
  METHODS
  Using a tissue microarray-based cohort of PDAC from 86 patients undergoing pancreaticoduodenectomy with curative intent and complete clinicopathological data available, we evaluated expression of the interleukin-6 receptor (IL-6R)/Jak/Stat pathway by immunohistochemistry. IL-6R, Jak, phospho (p)-Jak, Stat3, pStat3(Tyr705), and pStat3(Ser727) were assessed in PDAC and pancreatic intraepithelial neoplasia. A Cox regression multivariate analysis model was used to determine factors influencing survival. Activation of the IL-6R/Jak/Stat3 pathway was compared with the systemic inflammatory response as measured by serum C-reactive protein levels.
  
  
  RESULTS
  High pJak was associated with reduced overall survival in multivariate analysis when compared with those with moderate or low expression (p = 0.036; hazard ratio (HR) = 1.68) as was pStat3(Tyr705) (p < 0.001; HR = 2.66) independent of lymph node status and tumor grade. Patients with a combination of pJakhigh/pStat3(Tyr705) high expression had an especially poor prognosis (median survival of 8.8 months; 95 % CI, 4.4-13.2). While the IL-6R/Jak/Stat pathway did not correlate with serum C-reactive protein levels, high pStat3 expression was associated with a reduction in the density of the local tumoral immune response.
  
  
  CONCLUSIONS
  Activation of the Jak/Stat3 pathway via phosphorylation was associated with adverse outcome following resection of PDAC with curative intent supporting potential roles for pJak and pStat3 as prognostic biomarkers markers and therapeutic targets.
authors: West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, G31 2ER, UK.
authors: Simon M
authors: SM
authors: Denley
authors: Nigel B
authors: NB
authors: Jamieson
authors: Pamela
authors: P
authors: McCall
authors: Karin A
authors: KA
authors: Oien
authors: Jennifer P
authors: JP
authors: Morton
authors: C Ross
authors: CR
authors: Carter
authors: Joanne
authors: J
authors: Edwards
authors: Colin J
authors: CJ
authors: McKay
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000601:surgery*; D000368:Aged; D015153:Blotting, Western; D002097:C-Reactive Protein / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000601:surgery*; D018450:Disease Progression; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D053612:Janus Kinases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000601:surgery*; D016577:Pancreaticoduodenectomy; D011379:Prognosis; D016016:Proportional Hazards Models; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D018709:Statistics, Nonparametric; D015996:Survival Rate; D046888:Tissue Array Analysis
chemical_list: D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; D002097:C-Reactive Protein; D053612:Janus Kinases