Activation of the IL-6R/Jak/Stat Pathway is Associated with a Poor Outcome in Resected Pancreatic Ductal Adenocarcinoma

作者：Denley Simon M; Jamieson Nigel B^*; McCall Pamela; Oien Karin A; Morton Jennifer P; Carter C Ross; Edwards Joanne; McKay Colin J

来源：Journal of Gastrointestinal Surgery, 2013, 17(5): 887-898.

DOI：10.1007/s11605-013-2168-7

• IL-6
• Stat3
• Jak
• Pancreatic adenocarcinoma
• Inflammation
• Prognosis

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.
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.
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 pJak(high)/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.
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.

• 出版日期2013-5